Non-basic melanin concentrating hormone receptor-1 antagonists and methods

ABSTRACT

The present application provides compounds, including all stereoisomers, solvates, prodrugs and pharmaceutically acceptable forms thereof according to Formula I 
     
       
         
         
             
             
         
       
     
     wherein 
     
       
         
         
             
             
         
       
     
     R 1 , R 2 , R 3 , R 8 , and R 9  are defined herein. 
     Additionally, the present application provides pharmaceutical compositions containing at least one compound according to Formula I and optionally at least one additional therapeutic agent. Finally, the present application provides methods for treating a patient suffering from an MCHR-1 modulated disease or disorder such as, for example, obesity, diabetes, depression or anxiety by administration of a therapeutically effective dose of a compound according to Formula I.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. Ser. No. 12/141,228 filedJun. 18, 2008 which claims the benefit of U.S. Provisional ApplicationSer. No. 60/948,213 filed Jul. 6, 2007.

FIELD OF THE INVENTION

The present invention relates to non-basic melanin concentrating hormonereceptor-1 (MCHR1) antagonists, pharmaceutical compositions containingMCHR1 antagonists and methods of treating diabetes, obesity and relateddiseases employing such MCHR1 antagonists.

BACKGROUND OF THE INVENTION

Several lines of pharmacological and genetic evidence support the roleof Melanin Concentrating Hormone Receptor-1 (hereafter “MCHR1”) as amodulator of food intake and body weight. Central administration ofmelanin concentrating hormone (MCH) increases food intake and bodyweight both in rats and in mice. Chronic ICV infusion of MCH causesincreased food intake and ultimately obesity in mice, while infusion ofan MCH peptide antagonist blocks MCH-induced food intake and results inweight loss and decreased feeding in diet-induced obese mice.

The expression of both the MCH peptide and receptor are modulated bynutritional status. MCH mRNA is upregulated both in hyperphagic obesemice (ob/ob), and fasted animals. Targeted disruption of the gene forMCH peptide results in hypophagia and leanness. Disruption of the MCHR1gene causes leanness, altered metabolism, and hyperlocomotionaccompanied by mild hyperphagia. Conversely, over-expression of MCHpeptide results in hyperphagia, obesity and diabetes. Small moleculeMCHR1 antagonists have been shown to cause weight loss in rodent weightand feeding models after both oral and intraperitoneal administration;Eur. J. Pharmacol., 438:129-135 (2002), Nat. Med., 8:825-830 (2002),Eur. J. Pharmacol., 497:41-47 (2004).

Numerous non-peptide MCHR1 antagonists have been disclosed. The scope ofthe genus for each reflects a common perception regarding the criteriarequired for ligand recognition as MCHR1 agonists. A recent review ofMCHR1 patent disclosures emphasized the commonality of these structuresby the following description; “Ubiquitous throughout the MCH patentliterature are molecules consisting of a central scaffold to whichlinkers to an aryl or heteroaryl group and a basic amino functionalityare attached.” (Kowalski, T. J. et al., Expert Opin. Investig. Drugs,13:1113-1122 (2004)). Pharmacophore models of these geni consistentlyenvision a presumed prerequisite electrostatic interaction between abasic amine center of the antagonist ligand and aspartic acid 123 of thereceptor which presumably is envisaged to emulate the mandatoryinteraction between arginine 14 of MCH peptide agonists with asparticacid 123 of the MCHR1 receptor. (Ulven, T., J. Med. Chem., 48:5684-5697(2005)) However, incorporation of this basic amine in a MCHR1 antagonistincreases substantially the probability of binding to off-targetion-channels and biogenic amine receptors.

In accordance with the present invention, there is provided a series ofnovel high affinity selective MCHR1 antagonists for which bindingaffinity is not dependent upon inclusion of a basic amine functionalitythat is common to most of the disclosed MCHR antagonists. As aconsequence, the absence of the basic center greatly reduces theprobability of off-target interactions such as binding to other biogenicamine receptors as well as binding to ion channels such as the HERGreceptor in the heart. The reduction/abolition of affinity for the HERGreceptor is especially important since ligand occupancy is associatedwith initiation of fatal arrhythmias.

SUMMARY OF THE INVENTION

In one embodiment of the present invention, a compound of the Formula Ior a pharmaceutically acceptable salt thereof is provided

wherein

is a phenylene ring or a heteroaryl ring which is a monocyclic ring or abicyclic ring which contains one or two nitrogen atoms or one oxygenatom;

R¹ is Z—Y—X—, wherein

-   -   X is O, S,

-   -   Y is a bond, a 3- to 6-membered cycloalkyl, or an alkyl chain;        and    -   Z is aryl such as phenyl and naphthyl, or heteroaryl such as        pyridinyl, pyridimidinyl, pyrazinyl, benzimidazolyl,        benzothiazolyl, benzoxazolyl, or other “heteroaryl”;    -   R² is -E-G-(J)_(m), with m being an integer from 1 to 3;    -   E is O, S, or a bond;

G is lower alkyl, phenylalkyl, cycloalkyl, cycloalkylalkyl,alkylcycloalkyl, cycloalkoxy, alkylcycloalkoxy, or cycloalkoxyalkyl;

each J is independently hydrogen, hydroxyl, CN, —SO₂R⁷, —SR⁷, —SOR⁷,lower alkyl, lower alkoxy, CF₃, CF₃O—, —COOR⁵ (wherein R⁵ is H, C₁₋₃alkyl, or cycloalkyl), or —CO—NR^(5a)R⁶ wherein R^(5a) and R⁶ are eachindependently selected from H, C₁₋₃ alkyl, or cycloalkyl, or R^(5a) andR⁶ taken together can be propanediyl, butanediyl or pentanediyl to formwith the N atom to which they are attached a 4-, 5- or 6-membered cyclicamine, such as azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, orpiperazinyl, optionally substituted with substituents as set out for“heterocyclo”;

R⁷ is lower alkyl;

R³ is C₁₋₆ alkyl, cycloalkyl, C₁₋₆ alkoxy, halogen, hydrogen, —S—C₁₋₆alkyl, CN, CF₃O, or CF₃;

and wherein R² and R³ can be taken together to form a 5- to 7-memberedring which is saturated, unsaturated, or partially unsaturated and mayinclude an E heteroatom, which is O, or 0, 1 or 2 N atoms, which ring issubstituted with one or two of —O-G-(J)_(m) groups, wherein at least oneJ is OH, and optionally other substituents as set out for “alkyl”,“aryl”, or “heteroaryl”, such as alkyl and/or OH;

with the proviso that where

is a phenylene ring, E-G and R³ are not identical unsubstituted loweralkoxy groups, and when G is lower alkyl and J is H, R³ is not hydrogen;and

R⁸ and R⁹ are each independently hydrogen, halogen, or lower alkyl;

including esters thereof, prodrugs thereof, solvates thereof, and allstereoisomers thereof.

Any of the foregoing Z moieties may either be unsubstituted orsubstituted with 1, 2 or 3 of amino, halo, C₁₋₆ alkyl, C₁₋₃ alkylamino,di-C₁₋₃ alkylamino, C₁₋₃ alkoxy, C₁₋₃ thioalkyl, C₁₋₃ trifluoroalkoxy,trifluoromethyl, cycloalkyl, cycloalkoxy, or heteroaryl such as pyridylor substituted with any of the substituents as set out for “aryl”,“heteroaryl”, or “alkyl”.

Examples of substituents for the J group in the form of a cyclic amineinclude but are not limited to lower alkyl, lower alkoxy, OH, CF₃, orCF₃O, or other substituents as set out for “alkyl” and “heteroaryl”.

In a further aspect of the invention, there is provided a pharmaceuticalcomposition which contains a therapeutically effective amount of thecompound of the invention Formula I as defined above, in associationwith a pharmaceutically acceptable carrier or diluent.

There is also provided a method for the treatment of diabetes, obesityand other related conditions involving the MCHR1 in a mammal (such as ahuman, dog or cat) in need thereof, which includes the steps ofadministering to the mammal a therapeutically effective amount of thecompound of Formula I of the invention as defined above.

The invention also sets forth one or more methods for making thecompound of Formula I of the invention. In one embodiment, there isprovided a process for the preparation of the compound of Formula I ofthe invention, wherein the compound a

is reacted with the alkali metal salt of Z—Y—X¹H (b) (X¹═O or S),preferably Z—(CH₂)_(n)—X¹H (n=0, 1, 2 or 3).

In another embodiment of the invention, there is provided a process forthe preparation of the compound of Formula I of the invention, whereinthe compound c

is reacted with Z—Y—X¹H (b), preferably Z—(CH₂)_(n)—X¹H (n=0, 1, 2 or3), and preferably in the presence of an activating agent.

The present invention is directed to these, as well as other importantends, hereinafter described.

DETAILED DESCRIPTION OF THE INVENTION

The present application provides compounds, including all stereoisomers,solvates, prodrugs and pharmaceutically acceptable forms thereofaccording to Formula I. Additionally, the present application providespharmaceutical compositions containing at least one compound accordingto Formula I of the invention alone and optionally at least oneadditional therapeutic agent. Finally, the present application providesmethods for treating a patient suffering from an MCHR-1 modulateddisease or disorder such as, for example, obesity, diabetes, depressionor anxiety by administration of a therapeutically effective dose of acompound according to Formula I of the invention as defined above.

DEFINITIONS

Unless otherwise indicated, the term “lower alkyl” as may be employedherein alone or as part of another group includes both straight andbranched chain hydrocarbons containing 1 to 8 carbons, and the terms“alkyl”, “alk”, “alkyl chain”, “alkylene”, or “alkylene chain” as may beemployed herein alone or as part of another group includes both straightand branched chain hydrocarbons containing 1 to 20 carbons, preferably 1to 10 carbons, more preferably 1 to 8 carbons, in the normal chain, suchas methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl,hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl,2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, the variousbranched chain isomers thereof, and the like as well as such groupsincluding 2 free bonds and thus are linking groups, namely “alkylene”,as well as such groups including 1 to 4 substituents such as halo, forexample F, Br, Cl or I or CF₃, alkyl, alkoxy, aryl, aryloxy, aryl(aryl)or diaryl, arylalkyl, arylalkyloxy, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, cycloalkylalkyl, cycloalkylalkyloxy, hydroxy,hydroxyalkyl, acyl, alkanoyl, heteroaryl, heteroaryloxy,cycloheteroalkyl, arylheteroaryl, arylalkoxycarbonyl, heteroarylalkyl,heteroarylalkoxy, aryloxyalkyl, aryloxyaryl, alkylamido, alkanoylamino,arylcarbonylamino, nitro, cyano, thiol, haloalkyl, trihaloalkyl and/oralkylthio.

Unless otherwise indicated, the term “cycloalkyl” or “lower cycloalkyl”as may be employed herein alone or as part of another group includessaturated or partially unsaturated (containing 1 or 2 double bonds)cyclic hydrocarbon groups containing 1 to 3 rings, any one of which mayoptionally be a spiro substituted cycloalkyl, including monocycloalkyl,bicycloalkyl and tricycloalkyl, containing a total of 3 to 20 carbonsforming the rings, preferably 3 to 10 carbons, forming the ring andwhich may be fused to 1 or 2 aromatic rings as described for aryl, whichinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, cyclodecyl and cyclododecyl, cyclohexenyl,

as well as such groups including 2 free bonds and thus are linkinggroups, any of which groups may be optionally substituted with 1 to 4substituents such as halogen, alkyl, alkoxy, hydroxy, aryl, aryloxy,arylalkyl, cycloalkyl, alkylamido, alkanoylamino, oxo, acyl,arylcarbonylamino, nitro, cyano, thiol and/or alkylthio and/or any ofthe substituents set for “alkyl”.

Unless otherwise indicated, the term “cycloalkoxy” or “lowercycloalkoxy” as employed herein alone or as part of another group,represents a 4-, 5- or 6-membered saturated ring containing an oxygen inthe ring and includes

as well as such groups including 2 free bonds and thus are linkinggroups, and which may be optionally substituted with 1 or two of any ofthe substituents as set out for cycloalkyl.

The term “heterocyclo”, “heterocycle”, “heterocyclyl”, “heterocyclic” or“cycloheteroalkyl” ring, as may be used herein, represents anunsubstituted or substituted stable 4- to 7-membered monocyclic ringsystem which may be saturated or unsaturated, preferably saturated orpartially unsaturated, and which consists of carbon atoms, with one tofour heteroatoms selected from nitrogen, oxygen or sulfur, and whereinthe nitrogen and sulfur heteroatoms may optionally be oxidized, and thenitrogen heteroatom may optionally be quaternized, and including anybicyclic group in which the heterocyclic ring is fused to a benzenering. The heterocyclic ring may be attached at any heteroatom or carbonatom which results in the creation of a stable structure. Examples ofsuch heterocyclic groups include, but is not limited to, piperidinyl,piperazinyl, oxopiperazinyl, oxopiperidinyl, oxopyrrolidinyl,oxoazepinyl, azepinyl, pyrrolyl, pyrrolidinyl, furanyl, thienyl,pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl,pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl,isooxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl,isothiazolyl, thiadiazolyl, tetrahydropyranyl, thiamorpholinyl,thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, oxadiazolyl,

and other heterocycles described in Katritzky, A. R. et al., eds.,Comprehensive Heterocyclic Chemistry: The Structure, Reactions,Synthesis and Uses of Heterocyclic Compounds, Pergamon Press, New York,N.Y., publ. (1984); and Katritzky, A. R. et al., eds., ComprehensiveHeterocyclic Chemistry II: A Review of the Literature 1982-1995,Elsevier Science, Inc., Tarrytown, N.Y., publ. (1996); and referencestherein, as well as such groups including 2 free bonds and thus arelinking groups, as well as such groups optionally substituted with 1 to3 of F, Br, Cl or I or CF₃, alkyl, alkoxy, aryl, aryloxy, aryl(aryl) ordiaryl, arylalkyl, arylalkyloxy, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, cycloalkylalkyl, cycloalkylalkyloxy, hydroxy,hydroxyalkyl, acyl, alkanoyl, heteroaryl, heteroaryloxy,cycloheteroalkyl, arylheteroaryl, arylalkoxycarbonyl, heteroarylalkyl,heteroarylalkoxy, aryloxyalkyl, aryloxyaryl, alkylamido, alkanoylamino,arylcarbonylamino, nitro, cyano, thiol, haloalkyl, trihaloalkyl, and/oralkylthio.

The term “alkanoyl” as may be used herein alone or as part of anothergroup refers to alkyl linked to a carbonyl group.

The term “halogen” or “halo” as may be used herein alone or as part ofanother group refers to chlorine, bromine, fluorine, and iodine, withchlorine or fluorine being preferred.

The term “metal ion” refers to alkali metal ions such as sodium,potassium or lithium and alkaline earth metal ions such as magnesium andcalcium, as well as zinc and aluminum.

Unless otherwise indicated, the term “aryl” or “Aryl” as may be employedherein alone or as part of another group refers to monocyclic andbicyclic aromatic groups containing 6 to 10 carbons in the ring portion(such as phenyl or naphthyl including 1-naphthyl and 2-naphthyl) and mayoptionally include one to three additional rings fused to a carbocyclicring or a heterocyclic ring (such as aryl, cycloalkyl, heteroaryl orcycloheteroalkyl rings), for example

and as well as such groups including 2 free bonds and thus are linkinggroups, and may be optionally substituted through available carbon atomswith 1, 2, or 3 groups selected from hydrogen, halo, haloalkyl, alkyl,haloalkyl, alkoxy, haloalkoxy, alkenyl, trifluoromethyl,trifluoromethoxy, alkynyl, cycloalkyl-alkyl, cycloheteroalkyl,cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl, aryloxy,aryloxyalkyl, arylalkoxy, alkoxycarbonyl, arylcarbonyl, arylalkenyl,aminocarbonylaryl, arylthio, arylsulfinyl, arylazo, heteroarylalkyl,heteroarylalkenyl, heteroarylheteroaryl, heteroaryloxy, hydroxy, nitro,cyano, thiol, alkylthio, arylthio, heteroarylthio, arylthioalkyl,alkoxyarylthio, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl,arylaminocarbonyl, alkoxycarbonyl, aminocarbonyl, alkylcarbonyloxy,arylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, arylsulfinyl,arylsulfinylalkyl, arylsulfonylamino and arylsulfonaminocarbonyl and/orany of the substituents for “alkyl” set out herein.

Unless otherwise indicated, the term “heteroaryl” as may be used hereinalone or as part of another group refers to a 5- or 6-membered aromaticring which includes 1, 2, 3 or 4 hetero atoms such as nitrogen, oxygenor sulfur. Such rings may be fused to an aryl, cycloalkyl, heteroaryl orheterocyclyl and include possible N-oxides as described in Katritzky, A.R. et al., eds., Comprehensive Heterocyclic Chemistry: The Structure,Reactions, Synthesis and Uses of Heterocyclic Compounds, Pergamon Press,New York, N.Y., publ. (1984); and Katritzky, A. R. et al., eds.,Comprehensive Heterocyclic Chemistry II: A Review of the Literature1982-1995, Elsevier Science, Inc., Tarrytown, N.Y., publ. (1996); andreferences therein as well as such groups including 2 free bonds andthus are linking groups. Further, “heteroaryl”, as defined herein, mayoptionally be substituted with one or more substituents such as thesubstituents included above for “alkyl” and/or “aryl”. Examples ofheteroaryl groups include the following:

and the like.

Unless otherwise indicated, the term “lower alkoxy”, “alkoxy”, “aryloxy”or “aralkoxy” as may be employed herein alone or as part of anothergroup includes any of the above alkyl, aralkyl or aryl groups linked toan oxygen atom.

Unless otherwise indicated, the term “lower alkylthio”, alkylthio”,“arylthio” or “aralkylthio” as may be employed herein alone or as partof another group includes any of the above alkyl, aralkyl or aryl groupslinked to a sulfur atom.

The term “polyhaloalkyl” as may be used herein refers to an “alkyl”group as defined above which includes from 2 to 9, preferably from 2 to5, halo substituents, such as F or Cl, preferably F, such as CF₃CH₂, CF₃or CF₃CF₂CH₂.

The term “polyhaloalkyloxy” as may be used herein refers to an “alkoxy”or “alkyloxy” group as defined above which includes from 2 to 9,preferably from 2 to 5, halo substituents, such as F or Cl, preferablyF, such as CF₃CH₂O, CF₃O or CF₃CF₂CH₂O.

Unless otherwise indicated, the term “alkenyl” as used herein alone oras part of another group refers to straight or branched chain radicalsof 2 to 20 carbons, preferably 2 to 12 carbons, and more preferably 1 to8 carbons in the normal chain, which include one to six double bonds inthe normal chain, such as vinyl, 2-propenyl, 3-butenyl, 2-butenyl,4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 2-heptenyl, 3-heptenyl,4-heptenyl, 3-octenyl, 3-nonenyl, 4-decenyl, 3-undecenyl, 4-dodecenyl,4,8,12-tetradecatrienyl, and the like. Optionally, said alkenyl groupmay be substituted with one or substituents, such as those substituentsdisclosed for alkyl.

Unless otherwise indicated, the term “alkynyl” as used herein alone oras part of another group refers to straight or branched chain radicalsof 2 to 20 carbons, preferably 2 to 12 carbons and more preferably 2 to8 carbons in the normal chain, which include one triple bond in thenormal chain, such as 2-propynyl, 3-butynyl, 2-butynyl, 4-pentynyl,3-pentynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl,3-octynyl, 3-nonynyl, 4-decynyl, 3-undecynyl, 4-dodecynyl and the like.Optionally, said alkynyl group may be substituted with one orsubstituents, such as those substituents disclosed for alkyl.

The term “cycloalkenyl” as employed herein alone or as part of anothergroup refers to partially unsaturated cyclic hydrocarbons containing 3to 12 carbons, preferably 5 to 10 carbons and 1 or 2 double bonds.Exemplary cycloalkenyl groups include cyclobutenyl, cyclopentenyl,cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclohexadienyl, andcycloheptadienyl. Optionally, said cycloalkenyl group may be substitutedwith one or substituents, such as those substituents disclosed foralkyl.

The term “bicycloalkyl” as employed herein alone or as part of anothergroup includes saturated bicyclic ring groups such as, withoutlimitation, [3.3.0]bicyclooctane, [4.3.0]bicyclononane,[4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, and so forth.

The term “polycycloalkyl” as employed herein alone or as part of anothergroup includes two or more cycloalkyl ring systems, as defined herein,wherein at least one carbon atom is a part of at least two separatelyidentifiable ring systems. The polycycloalkyl group may contain bridgingbetween two carbon atoms, for example, bicyclo[1.1.0]butyl,bicyclo[3.2.1]octyl, bicyclo[5.2.0]nonyl, tricycl[2.2.1.0.sup.1 ]heptyl,norbornyl and pinanyl. The polycycloalkyl group may contain one or morefused ring systems, for example, decalinyl (radical from decalin) andperhydroanthracenyl. The polycycloalkyl group may contain a spiro union,in which a single atom is the only common member of two rings, forexample, spiro[3.4]octyl, spiro[3.3]heptyl and spiro[4.5]decyl.

The term “acyl” as employed herein by itself or part of another group,as defined herein, refers to an organic radical linked to a carbonyl

group; examples of acyl groups include a substituent group attached to acarbonyl, such as alkanoyl, alkenoyl, aroyl, aralkanoyl, heteroaryl,cycloalkanoyl, cycloheteroalkanoyl and the like.

“Optional” or “optionally” means that the subsequently described eventor circumstance may or may not occur, and that the description includes,without limitation, instances where said event or circumstance occursand instances in which it does not. For example, optionally substitutedalkyl means that alkyl may or may not be substituted by those groupsenumerated in the definition of substituted alkyl.

“Substituted,” as used herein, whether express or implied and whetherpreceded by “optionally” or not, means that any one or more hydrogen onthe designated atom (C, N, etc.) is replaced with a selection from theindicated group, provided that the designated atom's normal valency isnot exceeded, and that the substitution results in a stable compound.For instance, when a CH₂ is substituted by a keto substituent (═O), then2 hydrogens on the atom are replaced. Combinations of substituentsand/or variables are permissible only if such combinations result instable compounds. Further, when more than one position in a givenstructure may be substituted with a substituent selected from aspecified group, the substituents may be either the same or different atevery position.

The designation

or

attached to a ring or other group refers to a free bond or linkinggroup.

SPECIFIC EMBODIMENTS

The

group may be phenylene or a heteroaryl which is monocyclic or bicyclicand includes rings such as

with phenylene and pyridinyl being preferred.

The Formula I compound of the invention may have the structure

In the compound of Formula I of the invention, it is desired that

is phenylene or pyridinyl;

X is O or S; and/or

Y is a bond or an alkylene chain of 1, 2 or 3 atoms; and/or

Z is phenyl; or

Z is a heteroaryl such as pyridinyl or benzothiazole; and/or

R² is E-G-J; and/or

E is O or S; and/or

G is a lower alkyl or alkylcycloalkyl; and/or

J is H, OH, SO₂R⁷, lower alkyl, lower alkoxy, or CF₃, more preferablyOH; and/or

R³ is C₁₋₆ alkyl, C₁₋₆ alkoxy, H, or halo; and/or

R⁸ and R⁹ are independently H or CH₃; and/or

wherein R² and R³ can be taken together to form a 5- to 7-membered ringwhich is saturated, unsaturated, or partially unsaturated and mayinclude an E heteroatom, which is O, or 0, 1 or 2 N atoms, which ring issubstituted with one or two of —O-G-(J)_(m) groups, wherein at least oneJ is OH and optionally other substituents as set out for “alkyl”,“aryl”, or “heteroaryl”, such as alkyl and/or OH.

The above groups may be substituted as indicated herein.

Examples of the various groups of the compounds of Formula I of theinvention are set out below:

is phenylene or pyridinyl;

Z is

-   -   (1) aryl, such as phenyl or naphthyl, each of which is        optionally substituted with:        -   a) halogen such as Cl, Br or F,        -   b) alkyl such as CH₃, C₂H₅ or i-C₃H₇,        -   c) alkoxy such as CH₃O,        -   d) polyhaloalkyl such as CF₃,        -   e) polyhaloalkoxy such as CF₃O,        -   f) amino, alkylamino or dialkylamino such as

-   -   -   g) alkylthio such as CH₃S,        -   h) OH,        -   i) esters such as —COOCH₃, or        -   j) aryl such as phenyl,

    -   (2) monocyclic heteroaryl such as        -   a) pyridinyl,        -   b) pyrazinyl, or        -   c) pyrimidinyl,

    -   each of a), b) or c) being optionally substituted with alkyl        such as methyl, polyhaloalkyl such as trifluoromethyl, halogen        such as Cl or F, or alkoxy such as CH₃O;

    -   (3) benzothiazole optionally substituted with halo such as F,        Cl, alkoxy such as CH₃O,

    -   (4) benzoxazole optionally substituted with halo such as Cl,

    -   (5) benzimidazole,

    -   (6) thiazole optionally substituted with aryl such as phenyl,        and alkyl such as t-C₄H₉,

    -   (7) indanyl,

    -   (8) quinolinyl optionally substituted with CF₃, or

    -   (9) imidazolidinyl; and/or

Y is a bond or alkylene such as methylene, or ethylene or propylene;and/or

X is S, O, SO, or SO₂; and/or

J is

-   -   (1) H,    -   (2) —CO—NR^(5a)R⁶ where R^(5a) and R⁶ together with the N to        which they are attached form a pyrrolidinyl ring,    -   (3) OH,    -   (4) COOH,    -   (5) COOalkyl such as COOCH₃,    -   (6) SO₂R⁷ such as SO₂C₂H₅, or    -   (7) prodrug esters such as glycine

phosphate

and the corresponding Na salt thereof), and valine

and/or

m is 1 or 2; and/or

G is CH₂, (CH₂)₂, (CH₂)₃,

cycloalkyl such as

cycloalkoxy such as

or alkylcycloalkyl such as

and/or

E is O; and/or

R³ is H, alkoxy such as CH₃O, hydroxyalkyl such as HOCH₂CH₂—, alkyl suchas CH₃ or C₂H₅, halo such as F or Cl, CN, or hydroxyalkoxy such asHOCH₂CH₂O—; and/or

R² and R³ can be optionally taken together to form a 5- or 6-memberedunsaturated or aromatic ring containing one or two N atoms, which ringis optionally substituted with hydroxyalkyl such as

for example

or where R² and R³ can be optionally taken together to form a 6-memberedsaturated, unsaturated or partially unsaturated O-containing ring, whichring is optionally substituted with hydroxyalkyl such as alkyl such as

CH₃ and OH, for example

and/or

R⁸ is H, halo such as F and Cl, or alkyl such as methyl; and/or

R⁹ is H.

In a further embodiment of the compound of Formula I of the invention,X═O and

is phenylene or pyridinyl. In another embodiment, X═S and

is phenylene.

In a further embodiment in Formula I of the invention, Y is a bond. Alsoin a further embodiment, Y is methylene, ethylene or propylene. Inaddition, the alkyl chain or alkyl moiety in Y may be attached to theortho-position of Z to generate a bicyclic moiety. In this embodiment,the bicyclic moiety is preferably 1-indanyl or 2-indanyl when Z isphenyl.

In a further embodiment, Z is selected from phenyl, naphthyl, pyridinyl,pyrazinyl, benzimidazolyl, benzothiazolyl, and benzoxazolyl, preferablyphenyl and pyridinyl.

Furthermore, in the embodiment wherein R⁵ and R⁶ taken together form a4-, 5- or 6-membered cyclic amine, it is preferred that this componentbe selected from the group consisting of azetidinyl, pyrrolidinyl,piperidinyl, morpholinyl, and piperazinyl.

Also preferred is the embodiment wherein R³ is C₁-C₆ alkoxy. Especiallypreferred is the embodiment wherein R³ is C₁-C₃ alkoxy or C₁-C₃ alkyl.Even more preferably, R³ is methoxy or methyl.

In one embodiment of the invention, R¹ may be selected from the groupconsisting of:

It is also desirable that in Formula I, R² is —O—2-hydroxy-propane, R³is methoxy, and R¹ is selected from the group consisting of:

In another embodiment of the invention, it is desirable that

is phenylene;

R² is

or

R² and R³ can be optionally taken together to form a 5- or 6-memberedunsaturated or aromatic ring containing one or two N atoms, which ringis optionally substituted with hydroxyalkyl such as

for example

and

R³ is methoxy or methyl, and R¹ is selected from the group consistingof:

Also desired is the prodrug embodiment, hereinafter described, whereinin Formula I,

R² is E-G-hydroxyl-^(Pro-Drug) or more preferably

R³ is methoxy; and

R¹ is selected from

Also desired are compounds of Formula I wherein

is phenylene;

R¹ is Z—Y—X— wherein

-   -   X is S,    -   Y is an alkyl chain of 1 to 3 carbons or a bond,    -   Z is heteroaryl or phenyl,    -   each of which Z is optionally substituted with CF₃, CF₃O, or        halo;    -   R² is -E-G-J wherein    -   E is O,    -   G is lower alkyl such as

or alkylcycloalkyl such as

and

-   -   J is OH;

R³ is H, alkoxy such as CH₃O, or alkyl such as CH₃;

R⁸ and R⁹ are independently H or CH₃; and

R² and R³ can be optionally taken together to form a 5- or 6-memberedunsaturated or aromatic ring containing one or two N atoms, which ringis optionally substituted with hydroxyalkyl such as

for example

In still more preferred compounds of Formula I,

is phenylene;

X is S;

Y is a bond or (CH₂)₂;

E-G-J is

R³ is CH₃O or CH₃;

R⁸ and R⁹ are each H; and

R² and R³ can be optionally taken together to form a 5- or 6-memberedunsaturated or aromatic ring containing one or two N atoms, which ringis optionally substituted with hydroxyalkyl such as

for example

Some preferred compounds of the invention include the following:

Also desired are compounds of Formula I wherein

is

R¹ is Z—Y—X— wherein

-   -   X is S,    -   Y is an alkyl chain of 1 to 3 carbons such as (CH₂)₂ or a bond,    -   Z is heteroaryl such as 2-pyridyl or phenyl,    -   each of which Z is optionally substituted with CF₃, CF₃O, or        halo such as F,

so that R¹ can be selected from:

R² is -E-G-J wherein

-   -   E is O,    -   G is lower alkyl or alkylcycloalkyl, and    -   J is OH,    -   for example, R² is

R³ is alkoxy such as CH₃O, alkyl such as CH₃, or halo such as Cl; and

R⁸ and R⁹ are independently H or CH₃.

In still more desired compounds of Formula I,

is

X is S;

Y is a bond or (CH₂)₂;

Z is

E-G-J is

and

R³ is CH₃, H or Cl.

Methods of Preparation

The compounds of Formula I according to the various embodiments hereindescribed can be prepared as shown in the following non-limitingreaction schemes and description thereof, as well as relevant publishedliterature procedures that may be used by one skilled in the art.

Scheme 1 below portrays a generalized reaction sequence for thesynthesis of compounds of Formula I.

Compounds of Formula I, for which R¹ is Z—Y—O or Z—Y—S and R² does notcontain a tertiary alcohol, can be prepared by condensation of compoundsof Formula II in a solvent such as THF with alkali metal salts such asNa⁺ or K⁺ of compounds of Formula III. The alkali salts of compounds ofFormula III had been previously prepared by addition of compounds ofFormula III to a stirred dispersion of NaH or KH in a solvent such asTHF under an inert atmosphere of N₂ or Ar. Compounds of Formula II canbe prepared by treatment of compounds of Formula IV with thionylchloride in a solvent such as DMF. Compounds of Formula III arecommercially available or may be readily prepared by one skilled in thearts.

Alternatively, a general synthesis of compounds of Formula I, for whichR¹ is Z—Y—O, Z—Y—S or Z—Y—NR⁴H, entails condensation of compounds ofFormula IV with compounds of Formula III by stirring these components ina solvent such as DMF containingbenzotriazo-1-yl-oxy-trispyrrolidinophosphonium hexafluoroborate (PyBOP)as an activating agent, DMAP and a hindered amine such as Et(iPr)₂N.Other activating agents may be utilized by the skilled artisan.

Compounds of Formula IV can be prepared by heating compounds of FormulaV to 120-150° C. in microwave in a 1:1.1 mixture of HOAc/TFA. Compoundsof Formula V can be prepared by stirring compounds of Formula VI with2,2-dimethoxyethylamine in a solvent such as EtOAc. Compounds of FormulaVI can be prepared by treatment of compounds of Formula VII with ethyloxalyl chloride in a mixture of EtOAC and water containing a weak basesuch as potassium carbonate. Compounds of Formula VII are eithercommercially available or can be prepared as described in U.S. Ser. No.11/586,255.

Compounds of Formula I for which R¹ is Z—Y—SO or Z—Y—SO₂ can be preparedby treatment of compounds of Formula I where R¹ is Z—Y—S with one or twoequivalents of an oxidant such as m-chloroperbenzoic acid in a solventsuch as CH₂Cl₂.

Alternatively compounds of formula I can be prepared as outlined inScheme 2. by Cu catalyzed arylation of compounds of formula X by heatingX with aryl halides or iodides of formula XI in a solvent such asdioxane containing a cuprous salt such as cuprous iodide along withpotassium tribasic phosphate and a chelating agent such as N-methyl,N′-methyl ethylene diamine Compounds of formula X can be prepared byheating compounds of formula IX in TFA. Compounds of formula IX can beprepared by condensation of compound of Formula VIII with compounds ofFormula III by stirring these components in a solvent such as DMFcontaining benzotriazo-1-yl-oxy-trispyrrolidinophosphoniumhexafluoroborate (PyBOP) as an activating agent, DMAP and a hinderedamine such as Et(iPr)₂N. Compound of formula VIII is readily obtainedfrom p-methoxybenzyl amine utilizing the chemistry described inScheme 1. Aryl halides of formula XI are readily prepared by one skilledin the arts by alkylation of the corresponding commercially availablehalogenated phenol.

Other methods of preparing the compounds of Formula I are within thescope of the invention as well.

Prodrugs, Salts, Esters and Stereoisomers

The compounds of the invention also include “prodrugs”. The term“prodrug” as used herein encompasses both the term “prodrug esters” andthe term “prodrug ethers”. The term “prodrug esters” as employed hereinincludes esters and carbonates formed by reacting one or more hydroxylsof compounds of Formula I with either alkyl, alkoxy, or aryl substitutedacylating agents or phosphorylating agent employing procedures known tothose skilled in the art to generate acetates, pivalates,methylcarbonates, benzoates, amino acid esters, phosphates, half acidesters such as malonates, succinates or glutarates, and the like. Incertain embodiments, amino acid esters may be especially preferred.

Examples of such prodrug esters include

(R═H or isopropyl or other alkyl group) (for example,

(where R₁ is H or an alkali metal such as Na), that is

The term “prodrug ethers” include both phosphate acetals andO-glucosides. Representative examples of such prodrug ethers include

The compounds of Formula I can also be present as salts, which arefurther within the scope of this invention. Pharmaceutically acceptable(i.e., non-toxic, physiologically acceptable) salts are preferred. Ifthe compounds of Formula I have, for example, at least one basic center,they can form acid addition salts. These are formed, for example, withstrong inorganic acids, such as mineral acids, for example sulfuricacid, phosphoric acid (phosphate ester) or a hydrohalic acid, withorganic carboxylic acids, such as alkanecarboxylic acids of 1 to 4carbon atoms, for example acetic acid, which are unsubstituted orsubstituted, for example, by halogen as chloroacetic acid, such assaturated or unsaturated dicarboxylic acids, for example oxalic,malonic, succinic, maleic, fumaric, phthalic or terephthalic acid, suchas hydroxycarboxylic acids, for example ascorbic, glycolic, lactic,malic, tartaric or citric acid, such as amino acids, (for exampleaspartic acid, glutamic acid, glycine, valine, lysine, or arginine), orbenzoic acid, or with organic sulfonic acids, such as (C₁-C₄) alkyl orarylsulfonic acids which are unsubstituted or substituted, for exampleby halogen, for example methyl- or p-toluene-sulfonic acid.Corresponding acid addition salts can also be formed having, if desired,an additionally present basic center. The compounds of Formula I havingat least one acid group (for example COOH) can also form salts withbases. Suitable salts with bases are, for example, metal salts, such asalkali metal or alkaline earth metal salts, for example sodium,potassium or magnesium salts, or salts with ammonia or an organic amine,such as morpholine, thiomorpholine, piperidine, pyrrolidine, a mono, dior tri-lower alkylamine, for example ethyl, tert-butyl, diethyl,diisopropyl, triethyl, tributyl or dimethyl-propylamine, or a mono, dior trihydroxy lower alkylamine, for example mono, di or triethanolamine.Corresponding internal salts may furthermore be formed. Salts which areunsuitable for pharmaceutical uses but which can be employed, forexample, for the isolation or purification of free compounds of FormulaI or their pharmaceutically acceptable salts, are also included.

Preferred salts of the compounds of Formula I which contain a basicgroup include monohydrochloride, hydrogensulfate, methanesulfonate,phosphate, nitrate or acetate.

Preferred salts of the compounds of Formula I which contain an acidgroup include sodium, potassium and magnesium salts and pharmaceuticallyacceptable organic amines

All stereoisomers of the compounds of the invention are contemplated,either in admixture or in pure or substantially pure form. The compoundsof the present application can have asymmetric centers at any of thecarbon atoms including any one of the R substituents. Consequently,compounds of Formula I can exist in enantiomeric or diastereomeric formsor in mixtures thereof. The processes for preparation can utilizeracemates, enantiomers or diastereomers as starting materials.

When diastereomeric or enantiomeric products are prepared, they can beseparated by conventional methods for example, chromatographic orfractional crystallization.

Utility

The compounds of the present application can be administered to mammals,preferably humans, for the treatment of a variety of conditions anddisorders, including, but not limited to metabolic and eating disordersas well as conditions associated with metabolic disorders (e.g.,obesity, diabetes, arteriosclerosis, hypertension, polycystic ovarydisease, cardiovascular disease, osteoarthritis, dermatologicaldisorders, impaired glucose hemostasis, insulin resistance,hypercholesterolemia, hypertriglyceridemia, choletithiasis, dislipidemicconditions, bulimia nervosa and compulsive eating disorders); sleepdisorders; and psychiatric disorders, such as depression, anxiety,schizophrenia, substance abuse, cognition-enhancement and Parkinson'sdisease.

The compounds described in the present application could be used toenhance the effects of cognition-enhancing agents, such asacetylcholinesterase inhibitors (e.g., tacrine), muscarinic receptor-1agonists (e.g., milameline), nicotinic agonists, glutamic acid receptor(AMPA and NMDA) modulators, and nootropic agents (e.g., piracetam,levetiracetam). Examples of suitable therapies for treatment ofAlzheimer's disease and cognitive disorders for use in combination withthe compounds of the present application include donepezil, tacrine,revastigraine, 5HT6, gamma secretase inhibitors, beta secretaseinhibitors, SK channel blockers, Maxi-K blockers, and KCNQs blockers.

The compounds described in the present application could be used toenhance the effects of agents used in the treatment of Parkinson'sDisease. Examples of agents used to treat Parkinson's Disease include:levadopa with or without a COMT inhibitor, antiglutamatergic drugs(amantadine, riluzole), alpha-2 adrenergic antagonists such as idazoxan,opiate antagonists, such as naltrexone, other dopamine agonists ortransporter modulators, such as ropinirole, or pramipexole orneurotrophic factors such as glial derived neurotrophic factor (GDNF).

Pharmaceutical Combinations

The present application includes within its scope pharmaceuticalcompositions comprising, as an active ingredient, a therapeuticallyeffective amount of at least one of the compounds of Formula I, alone orin combination with a pharmaceutical carrier or diluent. Optionally,compounds of the present application can be used alone, in combinationwith other suitable therapeutic agents useful in the treatment of theaforementioned disorders including: anti-obesity agents; anti-diabeticagents, appetite suppressants; cholesterol/lipid-lowering agents,HDL-raising agents, cognition enhancing agents, agents used to treatneurodegeneration, agents used to treat respiratory conditions, agentsused to treat bowel disorders, anti-inflammatory agents; anti-anxietyagents; anti-depressants; anti-hypertensive agents; cardiac glycosides;and anti-tumor agents.

Such other therapeutic agent(s) may be administered prior to,simultaneously with, or following the administration of themelanin-concentrating hormone receptor (MCHR) antagonists in accordancewith the application.

Examples of suitable anti-obesity agents for use in combination with thecompounds of the present application include melanocortin receptor(MC4R) agonists, cannabinoid receptor modulators, growth hormonesecretagogue receptor (GHSR) antagonists, galanin receptor modulators,orexin antagonists, CCK agonists, GLP-1 agonists, and otherPre-proglucagon-derived peptides; NPY1 or NPY5 antagonist, NPY2 and NPY4modulators, corticotropin releasing factor agonists, histaminereceptor-3 (H3) modulators, aP2 inhibitors, PPAR gamma modulators, PPARdelta modulators, acetyl-CoA carboxylase (ACC) inhibitors, 11-β-HSD-1inhibitors, adinopectin receptor modulators; beta 3 adrenergic agonists,such as AJ9677 (Takeda/Dainippon), L750355 (Merck), or CP331648 (Pfizer)or other known beta 3 agonists as disclosed in U.S. Pat. Nos. 5,541,204,5,770,615, 5,491,134, 5,776,983 and 5,488,064, a thyroid receptor betamodulator, such as a thyroid receptor ligand as disclosed in WO 97/21993(U. Cal SF), WO 99/00353 (KaroBio) and WO 00/039077 (KaroBio), a lipaseinhibitor, such as orlistat or ATL-962 (Alizyme), serotonin receptoragonists, (e.g., BVT-933 (Biovitrum)), monoamine reuptake inhibitors orreleasing agents, such as fenfluramine, dexfenfluramine, fluvoxamine,fluoxetine, paroxetine, sertraline, chlorphentermine, cloforex,clortermine, picilorex, sibutramine, dexamphetamine, phentermine,phenylpropanolamine or mazindol, anorectic agents such as topiramate(Johnson & Johnson), CNTF (ciliary neurotrophic factor)/Axokine®(Regeneron), BDNF (brain-derived neurotrophic factor), leptin and leptinreceptor modulators, or cannabinoid-1 receptor antagonists, such asSR-141716 (Sanofi) or SLV-319 (Solvay).

Examples of suitable anti-diabetic agents for use in combination withthe compounds of the present application include: insulin secretagoguesor insulin sensitizers, which may include biguanides, sulfonyl ureas,glucosidase inhibitors, aldose reductase inhibitors, PPAR γ agonistssuch as thiazolidinediones, PPAR α agonists (such as fibric acidderivatives), PPAR δ antagonists or agonists, PPAR α/γ dual agonists,11-β-HSD-1 inhibitors, dipeptidyl peptidase IV (DP4) inhibitorsincluding saxagliptin, SGLT2 inhibitors including dapagliflozin andserglifozin, glycogen phosphorylase inhibitors, and/or meglitinides, aswell as insulin, and/or glucagon-like peptide-1 (GLP-1), GLP-1 agonist,incretin modulators, AMP kinase activators, glucocortical antagonists,fructose b is 1,6-phosphatase inhibitors, glucokinase inhibitors and/ora PTP-1B inhibitor (protein tyrosine phosphatase-1B inhibitor).

The antidiabetic agent may be an oral antihyperglycemic agent preferablya biguanide such as metformin or phenformin or salts thereof, preferablymetformin HCl. Where the antidiabetic agent is a biguanide, thecompounds of the present application will be employed in a weight ratioto biguanide within the range from about 0.001:1 to about 10:1,preferably from about 0.01:1 to about 5:1.

The antidiabetic agent may also preferably be a sulfonyl urea such asglyburide (also known as glibenclamide), glimepiride (disclosed in U.S.Pat. No. 4,379,785), glipizide, gliclazide or chlorpropamide, otherknown sulfonylureas or other antihyperglycemic agents which act on theATP-dependent channel of the beta-cells, with glyburide and glipizidebeing preferred, which may be administered in the same or in separateoral dosage forms. The oral antidiabetic agent may also be a glucosidaseinhibitor such as acarbose (disclosed in U.S. Pat. No. 4,904,769) ormiglitol (disclosed in U.S. Pat. No. 4,639,436), which may beadministered in the same or in a separate oral dosage forms.

The compounds of the present application may be employed in combinationwith a PPAR γ agonist such as a thiazolidinedione oral anti-diabeticagent or other insulin sensitizers (which has an insulin sensitivityeffect in NIDDM patients) such as rosiglitazone (SKB), pioglitazone(Takeda), Mitsubishi's MCC-555 (disclosed in U.S. Pat. No. 5,594,016),Glaxo-Wellcome's GL-262570, englitazone (CP-68722, Pfizer) ordarglitazone (CP-86325, Pfizer, isaglitazone (MIT/J&J), JTT-501(JPNT/P&U), L-895645 (Merck), R-119702 (Sankyo/WL), N,N-2344 (Dr.Reddy/NN), or YM-440 (Yamanouchi), preferably rosiglitazone andpioglitazone.

The compounds of the present application may also be employed with aPPARα/γ dual agonist such as MK-767/KRP-297 (Merck/Kyorin; as describedin Yajima, K. et al., Am. J. Physiol. Endocrinol. Metab., 284:E966-E971(2003)), AZ-242 (tesaglitazar; Astra-Zeneca; as described in Ljung, B.et al., J. Lipid Res., 43:1855-1863 (2002)); muraglitazar; or thecompounds described in U.S. Pat. No. 6,414,002.

The compounds of the present invention may be employed in combinationwith anti-hyperlipidemia agents, or agents used to treatarteriosclerosis. An example of an hypolipidemic agent would be an HMGCoA reductase inhibitor which includes, but is not limited to,mevastatin and related compounds as disclosed in U.S. Pat. No.3,983,140, lovastatin (mevinolin) and related compounds as disclosed inU.S. Pat. No. 4,231,938, pravastatin and related compounds such asdisclosed in U.S. Pat. No. 4,346,227, simvastatin and related compoundsas disclosed in U.S. Pat. Nos. 4,448,784 and 4,450,171. Other HMG CoAreductase inhibitors which may be employed herein include, but are notlimited to, fluvastatin, disclosed in U.S. Pat. No. 5,354,772,cerivastatin disclosed in U.S. Pat. Nos. 5,006,530 and 5,177,080,atorvastatin disclosed in U.S. Pat. Nos. 4,681,893, 5,273,995, 5,385,929and 5,686,104, pitavastatin (Nissan/Sankyo's nisvastatin (NK-104) oritavastatin), disclosed in U.S. Pat. No. 5,011,930,Shionogi-Astra/Zeneca rosuvastatin (visastatin (ZD-4522)) disclosed inU.S. Pat. No. 5,260,440, and related statin compounds disclosed in U.S.Pat. No. 5,753,675, pyrazole analogs of mevalonolactone derivatives asdisclosed in U.S. Pat. No. 4,613,610, indene analogs of mevalonolactonederivatives as disclosed in PCT application WO 86/03488,6-[2-(substituted-pyrrol-1-yl)-alkyl)pyran-2-ones and derivativesthereof as disclosed in U.S. Pat. No. 4,647,576, Searle's SC-45355 (a3-substituted pentanedioic acid derivative) dichloroacetate, imidazoleanalogs of mevalonolactone as disclosed in PCT application WO 86/07054,3-carboxy-2-hydroxy-propane-phosphonic acid derivatives as disclosed inFrench Patent No. 2,596,393, 2,3-disubstituted pyrrole, furan andthiophene derivatives as disclosed in European Patent Application No.0221025, naphthyl analogs of mevalonolactone as disclosed in U.S. Pat.No. 4,686,237, octahydronaphthalenes such as disclosed in U.S. Pat. No.4,499,289, keto analogs of mevinolin (lovastatin) as disclosed inEuropean Patent Application No. 0142146 A2, and quinoline and pyridinederivatives disclosed in U.S. Pat. Nos. 5,506,219 and 5,691,322. Inaddition, phosphinic acid compounds useful in inhibiting HMG CoAreductase suitable for use herein are disclosed in GB 2205837.

The squalene synthetase inhibitors suitable for use herein include, butare not limited to, α-phosphono-sulfonates disclosed in U.S. Pat. No.5,712,396, those disclosed by Biller, et al., J. Med. Chem.,31:1869-1871 (1998) including isoprenoid (phosphinyl-methyl)phosphonatesas well as other known squalene synthetase inhibitors, for example, asdisclosed in U.S. Pat. Nos. 4,871,721 and 4,924,024 and in Biller, S. A.et al., Current Pharmaceutical Design, 2:1-40 (1996).

In addition, other squalene synthetase inhibitors suitable for useherein include the terpenoid pyrophosphates disclosed by Ortiz deMontellano, P. et al., J. Med. Chem., 20:243-249 (1977), the farnesyldiphosphate analog A and presqualene pyrophosphate (PSQ-PP) analogs asdisclosed by Corey et al., J. Am. Chem. Soc., 98:1291-1293 (1976),phosphinylphosphonates reported by McClard, R. W. et al., J. Am. Chem.Soc., 109:5544 (1987) and cyclopropanes reported by Capson, T. L.,Ph.D., dissertation, June, 1987, Dept. Med. Chem., U. of Utah, Abstract,Table of Contents, pp. 16, 17, 40-43, 48-51, Summary.

Other hypolipidemic agents suitable for use herein include, but are notlimited to, fibric acid derivatives, such as fenofibrate, gemfibrozil,clofibrate, bezafibrate, ciprofibrate, clinofibrate and the like,probucol, and related compounds as disclosed in U.S. Pat. No. 3,674,836,probucol and gemfibrozil being preferred, bile acid sequestrants such ascholestyramine, colestipol and DEAE-Sephadex (SECHOLEX, POLICEXIDE) andcholestagel (Sankyo/Geltex), as well as lipostabil (Rhone-Poulenc),Eisai E-5050 (an N-substituted ethanolamine derivative), imanixil(HOE-402), tetrahydrolipstatin (THL), istigmastanylphosphorylcholine(SPC, Roche), aminocyclodextrin (Tanabe Seiyoku), Ajinomoto AJ-814(azulene derivative), melinamide (Sumitomo), Sandoz 58-035, AmericanCyanamid CL-277,082 and CL-283,546 (disubstituted urea derivatives),nicotinic acid (niacin), acipimox, acifran, neomycin, p-aminosalicylicacid, aspirin, poly(diallylmethylamine) derivatives such as disclosed inU.S. Pat. No. 4,759,923, quaternary amine poly(diallyldimethylammoniumchloride) and ionenes such as disclosed in U.S. Pat. No. 4,027,009, andother known serum cholesterol lowering agents.

The other hypolipidemic agent may be an ACAT inhibitor (which also hasanti-atherosclerosis activity) such as disclosed in, Drugs of theFuture, 24:9-15 (1999), (Avasimibe); Nicolosi et al., “The ACATinhibitor, Cl-1011 is effective in the prevention and regression ofaortic fatty streak area in hamsters”, Atherosclerosis (Shannon, Irel.),137(1):77-85 (1998); Ghiselli, G., “The pharmacological profile of FCE27677: a novel ACAT inhibitor with potent hypolipidemic activitymediated by selective suppression of the hepatic secretion ofApoB100-containing lipoprotein”, Cardiovasc. Drug Rev., 16(1):16-30(1998); Smith, C. et al., “RP 73163: a bioavailablealkylsulfinyl-diphenylimidazole ACAT inhibitor”, Bioorg. Med. Chem.Lett., 6(1):47-50 (1996); Krause, B. R. et al., Chapter 6: “ACATInhibitors: Physiologic Mechanisms for Hypolipidemic andAnti-Atherosclerotic Activities in Experimental Animals”, Inflammation:Mediators and Pathways, CRC Press, Inc., publ., Ruffolo, Jr., R. R. etal., eds., pp. 173-198 (1995); Sliskovic et al., “ACAT inhibitors:potential anti-atherosclerotic agents”, Curr. Med. Chem., 1(3):204-225(1994); Stout et al., “Inhibitors of acyl-CoA:cholesterol O-acyltransferase (ACAT) as hypocholesterolemic agents. 6. The firstwater-soluble ACAT inhibitor with lipid-regulating activity. Inhibitorsof acyl-CoA:cholesterol acyltransferase (ACAT). 7. Development of aseries of substituted N-phenyl-N′-[(1-phenylcyclopentyl)-methyl]ureaswith enhanced hypocholesterolemic activity”, Chemtracts: Org. Chem.,8(6):359-362 (1995), or TS-962 (Taisho Pharmaceutical Co. Ltd), as wellas F-1394, CS-505, F-12511, HL-004, K-10085 and YIC-C8-434.

The hypolipidemic agent may be an upregulator of LDL receptor activitysuch as MD-700 (Taisho Pharmaceutical Co. Ltd) and LY295427 (Eli Lilly).The hypolipidemic agent may be a cholesterol absorption inhibitorpreferably Schering-Plough's SCH48461 (ezetimibe) as well as thosedisclosed in Atherosclerosis, 115:45-63 (1995) and J. Med. Chem., 41:973(1998).

The other lipid agent or lipid-modulating agent may be a cholesteryltransfer protein inhibitor (CETP) such as Pfizer's CP-529,414 as well asthose disclosed in WO/0038722 and in EP 818448 (Bayer) and EP 992496,and Pharmacia's SC-744 and SC-795, as well as CETi-1 and JTT-705.

The hypolipidemic agent may be an ileal Na⁺/bile acid co-transporterinhibitor such as disclosed in Drugs of the Future, 24:425-430 (1999).The ATP citrate lyase inhibitor which may be employed in the combinationof the application may include, for example, those disclosed in U.S.Pat. No. 5,447,954.

The other lipid agent also includes a phytoestrogen compound such asdisclosed in WO 00/30665 including isolated soy bean protein, soyprotein concentrate or soy flour as well as an isoflavone such asgenistein, daidzein, glycitein or equol, or phytosterols, phytostanol ortocotrienol as disclosed in WO 2000/015201; a beta-lactam cholesterolabsorption inhibitor such as disclosed in EP 675714; an HDL upregulatorsuch as an LXR agonist, a PPAR α-agonist and/or an FXR agonist; an LDLcatabolism promoter such as disclosed in EP 1022272; a sodium-protonexchange inhibitor such as disclosed in DE 19622222; an LDL-receptorinducer or a steroidal glycoside such as disclosed in U.S. Pat. No.5,698,527 and GB 2304106; an anti-oxidant such as beta-carotene,ascorbic acid, α-tocopherol or retinol as disclosed in WO 94/15592 aswell as Vitamin C and an antihomocysteine agent such as folic acid, afolate, Vitamin B6, Vitamin B12 and Vitamin E; isoniazid as disclosed inWO 97/35576; a cholesterol absorption inhibitor, an HMG-CoA synthaseinhibitor, or a lanosterol demethylase inhibitor as disclosed in WO97/48701; a PPAR δ agonist for treating dyslipidemia; or a sterolregulating element binding protein-I (SREBP-1) as disclosed in WO2000/050574, for example, a sphingolipid, such as ceramide, or neutralsphingomyelenase (N-SMase) or fragment thereof. Preferred hypolipidemicagents are pravastatin, lovastatin, simvastatin, atorvastatin,fluvastatin, pitavastatin and rosuvastatin, as well as niacin and/orcholestagel.

The compounds of the present invention may also be employed incombination with anti-hypertensive agents. Examples of suitableanti-hypertensive agents for use in combination with the compounds ofthe present application include beta adrenergic blockers, calciumchannel blockers (L-type and/or T-type; e.g., diltiazem, verapamil,nifedipine, amlodipine and mybefradil), diuretics (e.g., chlorothiazide,hydrochlorothiazide, flumethiazide, hydroflumethiazide,bendroflumethiazide, methylchlorothiazide, trichloromethiazide,polythiazide, benzthiazide, ethacrynic acid tricrynafen, chlorthalidone,furosemide, musolimine, bumetanide, triamtrenene, amiloride,spironolactone), renin inhibitors, ACE inhibitors (e.g., captopril,zofenopril, fosinopril, enalapril, ceranopril, cilazopril, delapril,pentopril, quinapril, ramipril, lisinopril), AT-1 receptor antagonists(e.g., losartan, irbesartan, valsartan), ET receptor antagonists (e.g.,sitaxsentan, atrsentan and compounds disclosed in U.S. Pat. Nos.5,612,359 and 6,043,265), Dual ET/AII antagonist (e.g., compoundsdisclosed in WO 00/01389), neutral endopeptidase (NEP) inhibitors,vasopepsidase inhibitors (dual NEP-ACE inhibitors) (e.g., omapatrilatand gemopatrilat), and nitrates.

MCHR1 antagonists could also be useful in treating other diseasesassociated with obesity, including sleep disorders. Therefore, thecompounds described in the present application could be used incombination with therapeutics for treating sleep disorders. Examples ofsuitable therapies for treatment of sleeping disorders for use incombination with the compounds of the present application includemelatonin analogs, melatonin receptor antagonists, ML 1 B agonists, GABAreceptor modulators; NMDA receptor modulators, histamine-3 (H3) receptormodulators, dopamine agonists and orexin receptor modulators.

MCHR1 antagonists may reduce or ameliorate substance abuse or addictivedisorders. Therefore, combination of cannabinoid receptor modulatorswith agents used to treat addictive disorders may reduce the doserequirement or improve the efficacy of current addictive disordertherapeutics. Examples of agents used to treat substance abuse oraddictive disorders are: selective serotonin reuptake inhibitors (SSRI),methadone, buprenorphine, nicotine and bupropion.

MCHR1 antagonists may reduce anxiety or depression; therefore, thecompounds described in this application may be used in combination withanti-anxiety agents or antidepressants. Examples of suitableanti-anxiety agents for use in combination with the compounds of thepresent application include benzodiazepines (e.g., diazepam, lorazepam,oxazepam, alprazolam, chlordiazepoxide, clonazepam, chlorazepate,halazepam and prazepam), 5HT1A receptor agonists (e.g., buspirone,flesinoxan, gepirone and ipsapirone), and corticotropin releasing factor(CRF) antagonists.

Examples of suitable classes of anti-depressants for use in combinationwith the compounds of the present application include norepinephrinereuptake inhibitors (tertiary and secondary amine tricyclics), selectiveserotonin reuptake inhibitors (SSRIs) (fluoxetine, fluvoxamine,paroxetine and sertraline), monoamine oxidase inhibitors (MAOIs)(isocarboxazid, phenelzine, tranylcypromine, selegiline), reversibleinhibitors of monoamine oxidase (RIMAs) (moclobemide), serotonin andnorepinephrine reuptake inhibitors (SNRIs) (venlafaxine), corticotropinreleasing factor (CRF) receptor antagonists, alpha-adrenoreceptorantagonists, and atypical antidepressants (bupropion, lithium,nefazodone, trazodone and viloxazine).

The combination of a conventional antipsychotic drug with a MCHR1antagonist could also enhance symptom reduction in the treatment ofpsychosis or mania. Further, such a combination could enable rapidsymptom reduction, reducing the need for chronic treatment withantipsychotic agents. Such a combination could also reduce the effectiveantipsychotic dose requirement, resulting in reduced probability ofdeveloping the motor dysfunction typical of chronic antipsychotictreatment.

Examples of suitable antipsychotic agents for use in combination withthe compounds of the present application include the phenothiazine(chlorpromazine, mesoridazine, thioridazine, acetophenazine,fluphenazine, perphenazine and trifluoperazine), thioxanthine(chlorprothixene, thiothixene), heterocyclic dibenzazepine (clozapine,olanzepine and aripiprazole), butyrophenone (haloperidol),diphenylbutylpiperidine (pimozide) and indolone (molindolone) classes ofantipsychotic agents. Other antipsychotic agents with potentialtherapeutic value in combination with the compounds in the presentapplication include loxapine, sulpiride and risperidone.

Combination of the compounds in the present application withconventional antipsychotic drugs could also provide an enhancedtherapeutic effect for the treatment of schizophrenic disorders, asdescribed above for manic disorders.

As used here, schizophrenic disorders include paranoid, disorganized,catatonic, undifferentiated and residual schizophrenia, schizophreniformdisorder, schizoaffective disorder, delusional disorder, brief psychoticdisorder and psychotic disorder not specified. Examples of suitableantipsychotic drugs for combination with the compounds in the presentapplication include the antipsychotics mentioned above, as well asdopamine receptor antagonists, muscarinic receptor agonists, 5HT2Areceptor antagonists and 5HT2A/dopamine receptor antagonists or partialagonists (e.g., olanzepine, aripiprazole, risperidone, ziprasidone).

Dosage Forms

The compounds of the present invention can be administered in oraldosage form The dosage form for said pharmaceutical composition includessuch oral dosage forms as granules, powders, tablets, capsules, syrups,emulsions, suspensions, etc. and such non-oral dosage forms asinjections (e.g., subcutaneous, intravenous, intramuscular andintraperitoneal injections), drip infusions, external application forms(e.g., nasal spray preparations, transdermal preparations, ointments,etc.), and suppositories (e.g., rectal and vaginal suppositories).

These dosage forms can be manufactured by the per se known techniqueconventionally used in pharmaceutical procedures. The specificmanufacturing procedures are as follows.

To manufacture an oral dosage form, an excipient (e.g., lactose,sucrose, starch, mannitol, etc.), a disintegrator (e.g., calciumcarbonate, carboxymethylcellulose calcium, etc.), a binder (e.g.,α-starch, gum arabic, carboxymethylcellulose, polyvinylpyrrolidone,hydroxypropylcellulose, etc.), and a lubricant (e.g., talc, magnesiumstearate, polyethylene glycol 6000, etc.), for instance, are added tothe active component or components and the resulting composition iscompressed. Where necessary, the compressed product is coated, by theper se known technique, for masking the taste or for enteric dissolutionor sustained release. The coating material that can be used includes,for instance, ethylcellulose, hydroxymethylcellulose, polyoxyethyleneglycol, cellulose acetate phthalate, hydroxypropylmethylcellulosephthalate, and Eudragit (Rohm & Haas, Germany, methacrylic-acryliccopolymer).

Injections can be manufactured typically by the following procedure. Theactive component or components are dissolved, suspended or emulsified inan aqueous vehicle (e.g., distilled water, physiological saline,Ringer's solution, etc.) or an oily vehicle (e.g., vegetable oil such asolive oil, sesame oil, cottonseed oil, corn oil, etc. or propyleneglycol) together with a dispersant, e.g., Tween 80 (Atlas Powder,U.S.A.), HCO 60 (Nikko Chemicals), polyethylene glycol,carboxymethylcellulose, sodium alginate, etc.), a preservative (e.g.,methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, benzyl alcohol,chlorobutanol, phenol, etc.), an isotonizing agent (e.g., sodiumchloride, glycerol, sorbitol, glucose, inverted sugar, etc.) and otheradditives. If desired, a solubilizer (e.g., sodium salicylate, sodiumacetate, etc.), a stabilizer (e.g., human serum albumin), a soothingagent (e.g., benzalkonium chloride, procaine hydrochloride, etc.) andother additives can also be added.

A dosage form for external application can be manufactured by processingthe active component or components into a solid, semi-solid or liquidcomposition. To manufacture a solid composition, for instance, theactive component or components, either as they are or in admixture withan excipient (e.g., lactose, mannitol, starch, microcrystallinecellulose, sucrose, etc.), a thickener (e.g., natural gums, cellulosederivatives, acrylic polymers, etc.), etc., are processed into powders.The liquid composition can be manufactured in substantially the samemanner as the injections mentioned above. The semi-solid composition ispreferably provided in a hydrous or oily gel form or an ointment form.These compositions may optionally contain a pH control agent (e.g.,carbonic acid, phosphoric acid, citric acid, hydrochloric acid, sodiumhydroxide, etc.), and a preservative (e.g., p-hydroxybenzoic acidesters, chlorobutanol, benzalkonium chloride, etc.), among otheradditives.

Suppositories can be manufactured by processing the active component orcomponents into an oily or aqueous composition, whether solid,semi-solid or liquid. The oleaginous base that can be used includes, forinstance, higher fatty acid glycerides [e.g., cacao butter, Witepsols(Dinamit-Nobel), etc.], medium-chain fatty acids [e.g., Migriols(Dinamit-Nobel), etc.], vegetable oils (e.g., sesame oil, soybean oil,cotton-seed oil, etc.), etc. The water-soluble base includes, forinstance, polyethylene glycols propylene glycol, etc. The hydrophilicbase includes, for instance, natural gums, cellulose derivatives, vinylpolymers, and acrylic polymers, etc.

Dosages

The dosage of the pharmaceutical composition of the present inventionmay be appropriately determined with reference to the dosagesrecommended for the respective active components and can be selectedappropriately according to the recipient, the recipient's age and bodyweight, current clinical status, administration time, dosage form,method of administration, and combination of the active components,among other factors. For example, the dosage of the compound of FormulaI of the invention for a human adult can be selected from the clinicaloral dose range of 0.01 to 30 mg/kg body weight (preferably 0.05 to 10mg/kg body weight, more preferably 0.05 to 5 mg/kg body weight) or theclinical parenteral dose range of 0.005 to 10 mg/kg body weight(preferably 0.01 to 10 mg/kg body weight, more preferably 0.01 to 1mg/kg body weight) or 1 to 1000 mg/day. The other active component orcomponents having different modes of action for use in combination canalso be used in dose ranges selected by referring to the respectiverecommended clinical dose ranges. Administration is generally carriedout in a single dose/day or in divided doses, for example, 2 to 4 timesa day.

ABBREVIATIONS

The following abbreviations may be employed herein:

Ph=phenylBn=benzylt-Bu=tertiary butylMe=methylEt=ethylTMS=trimethylsilylTBS=tert-butyldimethylsilylEt₂O=diethyl etherEtOAc=ethyl acetateMeOH=methanolEtOH=ethanoli-PrOH=isopropanolHOAc or AcOH=acetic acidi-Pr₂NEt=diisopropylethylamineEt₃N=triethylamineDMAP=4-dimethylaminopyridineNaBH₄=sodium borohydriden-BuLi=n-butyllithiumPd/C=palladium on carbonKOH=potassium hydroxideNaOH=sodium hydroxideLiOH=lithium hydroxideK₂CO₃=potassium carbonateNaHCO₃=sodium bicarbonateAr=argonN₂=nitrogenmin=minute(s)h or hr=hour(s)L=litermL=milliliterμL=microliterg=gram(s)mg=milligram(s)mol=molesmmol=millimole(s)meq=milliequivalentRT=room temperaturesat or sat' d=saturatedaq.=aqueousTLC=thin layer chromatographyHPLC=high performance liquid chromatographyLC/MS=high performance liquid chromatography/mass spectrometryMS or Mass Spec=mass spectrometryNMR=nuclear magnetic resonancemp=melting point

EXAMPLES

The following examples are provided to illustrate various preferredembodiments of the invention, and should not be construed as limitingthe scope thereof.

General Experimental Information Section

In the following examples, nomenclature conforms to either IUPAC or CASguidelines; was generated using (or is consistent with) the Autonom®module (version 2.1) distributed with ChemDraw Ultra 6.0®; or are takenfrom vendor literature.

brine=saturated aqueous sodium chlorideDIC=diisopropylcarbodiimide

DMF=N,N-dimethylformamide HOBT=Hydroxybenzotriazole

PyBOP=benzotriazo-1-yl-oxy-trispyrrolidinophosphonium hexafluoroborateTFA=trifluoroacetic acidTHF=tetrahydrofuranylWSC=1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride

Analytical Chromatography Methods

HPLC: column:

Method 1: Phenom-Luna (ODS) S-5, 4.6 mm×50 mm; flow-5.0 mL/min.;detection at 220 nm; solvent-A=10% methanol/water+0.2% phosphoric acid,B=90% methanol/water+0.2% phosphoric acid; gradient-linear, 0% B to 100%B over 4 min and 100% B for 1 min.

Method 2: YMC Combiscreen S-5, 4.6 mm×50 mm; flow-4.0 mL/min.; detectionat 220 nm; solvent-A=10% methanol/water+0.2% phosphoric acid, B=90%methanol/water+0.2% phosphoric acid; gradient-linear, 0% B to 100% Bover 4 min and 100% B for 1 min.

LC MS: column-Phen-Luna (S5 ODS column) 4.6 mm×30 mm; detection at 220nm; flow-4 mL/min; solvent-A=10% methanol/water+0.1% TFA, B=90%methanol/water+0.1% TFA; linear gradient, 0% B to 100% B over 2 min and100% B for 1 min.

Preparative HPLC Chromatography Method

Phenomenex Luna C18, S5, 21×100 mm; flow-20 mL/min, detection at 220 nm;solvent-A=10% methanol/water+0.1% TFA, B=90% methanol/water+0.1% TFA;gradient-linear, 10% B to 90% B over 20 min.

General Experimental Procedures for Preparation of3-(Arylthio)-1-(aryl)pyrazin-2(1H)-one Preparation of 1-Arylpyrazine-2,3(1H,4H)-dione Part A

Ethyl oxalyl chloride (7.8 g, 6.8 mL, 57 mmol) was added to a mixture of3,4-dimethoxyaniline (4.4 g, 29 mmol) and K₂CO₃ (14 g, 140 mmol) inEtOAc (44 mL) and water (12 mL) at 0° C. After stirring at 0° C. for 10min, water (18 mL) was added; whereupon the mixture was transferred to aseparatory funnel and extracted with EtOAc (2×40 mL). The combined EtOAcwere filtered through Na₂SO₄ and evaporated to about 30 mL. Afteraddition of 2,2-dimethoxyethylamine (3.8 g, 3.9 mL, 36 mmol), thereaction was stirred at ambient temperature overnight. The resultantwhite solid was filtered and then washed with hexane to affordN1-(2,2-dimethoxyethyl)-N2-(3,4-dimethoxyphenyl)oxalamide as a lightpurple-grey solid (6.3 g, 71% yield). HPLC 33% 2.47 min and 63% at 2.79min. LC MS 1.37 min (M+1=281 and 335). H-NMR (CDCl₃) 9.15 (broad s, 1H),7.76 (broad s, 1H), 7.41 (d, J=2.4 Hz, 1H), 7.06 (dd, J=2.4, 8.7 Hz,1H), 6.85 (d, J=8.7 Hz, 1H), 4.45 (t, J=5.5 Hz, 1H), 3.90 (s, 3H), 3.88(s, 3H), 3.52 (t, J=5.5 Hz, 2H), 3.42 (s, 6H).

Part B

After addition of trifluoroacetic acid (0.12 mL, 1.7 mmol) to a mixtureof the aryl oxalamide prepared in Part A (0.50 g, 1.6 mmol) in aceticacid (1.0 mL), the resulting solution was heated to 125° C. for 20 minusing a microwave. Following evaporation of the solvent, the residue wastriturated with EtOAc to afford1-(3,4-dimethoxyphenyl)pyrazine-2,3(1H,4H)-dione as a white solid (1.1g, 92% yield). HPLC 1.83 min. LC MS 1.20 min (M+1=249). H-NMR (CD₃OD)7.06 (m, 2H), 6.97 (m, 1H), 6.56 (d, J=5.7 Hz, 1H), 6.45 (d, J=5.7 Hz,1H), 3.89 (s, 3H), 3.85 (s, 3H).

Preparation of Desired Substituted 3-thio-1-aryl-pyrazin-2(1H)-oneMethod 1 Part C

Thionyl chloride (0.28 g, 0.17 mL, 2.4 mmol) was slowly added to astirred solution of the 1-aryl pyrazine-2,3(1H,4H)-dione prepared inPart B (0.54 g, 2.2 mmol) in EtOAc (0.88 mL) and DMF (0.44 mL) at 45° C.After stirring at 55 to 60° C. for 2 h, the reaction was transferred toa separatory funnel, diluted with EtOAc and 2N KHCO₃ and extracted withEtOAc (2×). The combined organic layers were washed with 2N KHCO₃ andwater; whereupon, the combined aqueous layers were extracted withCH₂Cl₂. All of the organic layers were combined prior to drying overMgSO₄ to afford 3-chloro-1-(3,4-dimethoxyphenyl)pyrazin-2(1H)-one (0.34g, 59% yield). HPLC 2.33 min. LC MS 1.00 min (M+1=267/269). Thechloropyrazinone was used in the subsequent steps without furtherpurification.

Part D

4-Chlorobenzylmercaptan (71 mg, 0.059 mL, 0.45 mmol) was added to astirred THF (1.0 mL) suspension of sodium hydride (60% oil dispersion,18 mg, 0.45 mmol), that had been previously washed with hexane 3×. Thereaction was stirred at ambient temperature for 20 min until it became asolid mass; whereupon, the chloropyrazinone prepared in Part C (100 mg,0.38 mmol) in THF (5 mL) was added resulting in gas evolution. Afterstirring at ambient temperature for 40 min, the reaction was dilutedwith CH₂Cl₂/H₂O, extracted with CH₂Cl₂ (2×) and dried over MgSO₄ toafford 220 mg of crude product after evaporation of the solvent. Thedesired was purified by chromatography on silica gel (12 g) employinggradient elution (0-100% EtOAc/hexane over 12 min) to elute the desired3-(4-chlorobenzylthio)-1-(3,4-dimethoxyphenyl)pyrazin-2(1H)-one (130 mg,89% yield).

Method 2

A solution of the 1-aryl pyrazine-2,3(1H,4H)-dione prepared in Part B(67 mg, 0.27 mmol), diisopropylethyl amine (0.15 mL, 0.81 mmol), pyBOP(0.23 g, 0.46 mmol), and dimethylaminopyridine (13 mg) in DMF (1.2 mL)was stirred at ambient temperature for 15 min. After addition of2-pyridylethyl mercaptan (28 mg, 0.40 mmol), the reaction was stirred atambient temperature for 2.5 h prior to quenching by addition of H₂O andextraction with EtOAc. The EtOAc extracts were washed with water (2×),brine, dried over MgSO₄ and concentrated to yield 204 mg of crudeproduct. Chromatography on silica employing a gradient elution withhexane/EtOAc afforded the desired product1-(3,4-dimethoxyphenyl)-3-(2-(pyrazin-2-yl)ethylthio)pyrazin-2(1H)-one(17 mg, 17% yield).

Method 2a

The same procedure was employed as that described in Method 2 exceptthat the reaction was run for 18 hr.

Method 3

Following preparation of the oxalamide as described in Part A, ringclosure can be effected by prolonged thermal heating in TFA/HOAc at 78°C. for 1d. In the case of 3-methoxy-4-(2-(pyrrolidin-1-yl)ethoxy)anilinewhich contained a basic amine, the reaction was brought to pH 6 to 7with saturated NaHCO₃ and then evaporated in vacuo. The residue wasabsorbed on silica gel and purified by flash chromatography (5 to 15% 2NNH₃ in MeOH/CH₂Cl₂) to afford the desired 1-arylpyrazine-2,3(1H,4H)-dione in 36% yield. This material was subsequentlyconverted to final product following the procedure described in Method2.

Method 4

If the oxalamide as described in Part A contained a primary or secondaryalcohol, prolonged thermal heating in TFA/HOAc at 78° C. for 1 day notonly effected ring closure but also converted the alcohol moiety to anacetate. The resulting 1-aryl pyrazine-2,3(1H,4H)-dione was converted tothe desired 3-thio substituted-1-arylpyrazin-2-one employing Method 1.Following workup and purification as described in Method 1, theacetylated product was converted to the desired 3-thiosubstituted-1-arylpyrazin-2-one (19 mg, 0.041 mmol) bearing a freehydroxyl by dissolution in MeOH (1.0 mL) and H₂O (0.1 mL) and stirringat ambient temperature for 1 h after addition of potassium carbonate (30mg). The reaction was then diluted with CH₂Cl₂/H₂O prior to extractionwith CH₂Cl₂ (2×). After drying the combined organic layers over MgSO₄,concentration afforded the desired final product (16 mg, 93% yield).

Method 5

For weakly nucleophilic thiols more forcing conditions were requiredeffect PyBOP mediated conversion of the 1-aryl pyrazine-2,3(1H,4H)-dioneto a 3-thio substituted-1-arylpyrazin-2-ones. Accordingly, a DMFsolution (0.4 mL) containing the 1-aryl pyrazine-2,3(1H,4H)-dioneprepared in Part B (92 mg, 0.30 mmol), PyBOP (0.27 g, 0.53 mmol) anddiisopropylethylamine (0.16 mL, 0.9 mmol) was stirred for 3 h beforeaddition of a DMF solution prepared by stirring5-methoxybenzo[d]thiazole-2-thiol (296 mg, 1.502 mmol) with NaH (60.1mg, 1.502 mmol, rinsed with hexane 2×) in DMF (0.2 mL) at ambienttemperature for 10 min. After stirring at ambient temperature for 7days, the reaction mixture was diluted with EtOAc and washedsequentially with water (2×) and brine prior to drying over MgSO₄. Afterevaporation of the solvent, CH₂Cl₂ (10 mL) was added to the 0.30 g ofcrude product. Filtration to remove any residual solids followed byevaporation of the filtrate afforded 0.10 g crude product. Finalpurification required flash chromatography on 12 g silica gel usinggradient elution (0 to 100% EtOAc/CH₂Cl₂) followed by preparatory HPLC(YMC S5 ODS 20×100 mm, 20 mL/min, 30 to 100% B in A over 10 min,.Solvent A=10% MeOH/H₂O-0.1% TFA, Solvent B=90% MeOH/H₂O-0.1% TFA) toafford pure desired product (6.3 mg, 4% yield).

Method 6

General Experimental Procedures for Preparation of1-(4-(2-Hydroxy-2-methylpropoxy)-3-methylphenyl)-3-(4-(trifluoromethoxy)phenylthio)pyrazin-2(1H)-one

Part A. N1-(2,2-Dimethoxyethyl)-N2-(4-methoxybenzyl)oxalamide

To a mixture of (4-methoxyphenyl)methanamine (9.90 g, 72.2 mmol) in THF(40 mL) was slowly added ethyl 2-chloro-2-oxoacetate (10.84 g, 79 mmol).After stirring the reaction at RT for 15 min, a solution of2,2-dimethoxyethanamine (9.10 g, 87 mmol) and N,N-diisopropylethylamine(37.8 mL, 217 mmol) in EtOAc (40.0 mL) was added. The reaction washeated at reflux for 18 hours; whereupon, after cooling to RT, saturatedNaHCO₃ (50 ml) was added and the mixture extracted with EtOAc (50 ml).The EtOAc layer was dried over Na₂SO₄ and concentrated. The crudeproduct was purified by silica gel chromatography employing a solventgradient (CH₂Cl₂ to 5% MeOH/CH₂Cl₂) to eluteN1-(2,2-dimethoxyethyl)-N2-(4-methoxybenzyl)oxalamide (7.50 g, 25.3mmol, 35.1% yield) as white solid. 1H NMR (400 MHz, chloroform-d) δ ppm9.07 (1H, s), 7.69 (1H, t, J=5.65 Hz), 7.59 (1H, d, J=8.78 Hz), 6.74(1H, d, J=8.78 Hz), 4.46 (1H, t, J=5.40 Hz), 3.79 (2H, s), 3.53 (2H, t),3.44 (6H, s), 2.23 (6H, d, J=5.27 Hz), 1.37 (6H, s).

Part B. 3-Hydroxy-1-(4-methoxybenzyl)pyrazin-2(1H)-one

A solution of N1-(2,2-dimethoxyethyl)-N2-(4-methoxybenzyl)oxalamide (7.5g, 25.3 mmol) and TFA (2.340 mL, 30.4 mmol) in AcOH (160 mL) was stirredat 135° C. in a seal tube for 1.5 hours. After cooling to RT and removalof the volatiles under vacuum, ethyl ether (150 ml) and sat. aq. NaHCO₃solution (150 ml) were added. The resulting precipitate was collected byfiltration, washed with H₂O (50 ml) and ether (50 ml) prior to dryingunder high vacuum to yield3-hydroxy-1-(4-methoxybenzyl)pyrazin-2(1H)-one (5.30 g, 21.68 mmol, 86%yield) as brown solid. 1H NMR (400 MHz, DMSO-d₆) δ ppm 11.17 (1H, br.s.), 7.18 (2H, d), 6.81 (2H, d), 6.46 (1H, d, J=5.77 Hz), 6.23 (1H, br.s.), 4.74 (2H, s), 3.24 (1H, s).

Part C.1-(4-Methoxybenzyl)-3-(4-(trifluoromethoxy)phenylthio)pyrazin-2(1H)-one

A mixture of 3-hydroxy-1-(4-methoxybenzyl)pyrazin-2(1H)-one (2.0 g, 8.61mmol), PyBOP (7.84 g, 15.07 mmol) and N,N-diisopropylethylamine (4.51mL, 8 mmol) in DMF (40 mL) was stirred at RT under N₂ for 3 hourswhereupon 4-(trifluoromethoxy)benzenethiol (2.007 g, 10.33 mmol) wasadded. After having stirred for 18 additional hours, the reaction wasdiluted with saturated aq. NaHCO₃ (65 ml) and was then extracted withEtOAc (60 ml). The EtOAc layer was dried over Na₂SO₄ and concentrated.The crude product was purified by silica gel chromatography employing asolvent gradient (hexane to 75% EtOAc/hexane) to elute1-(4-methoxybenzyl)-3-(4-(trifluoromethoxy)phenylthio)pyrazin-2(1H)-one(2.76 g, 6.42 mmol, 74.6% yield) as white solid. 1H NMR (400 MHz,chloroform-d) δ ppm 7.58 (2H, d, J=8.78 Hz), 7.21-7.35 (4H, m), 7.02(1H, d, J=4.52 Hz), 6.90 (2H, d, J=8.78 Hz), 6.85 (1H, d, J=4.27 Hz),5.03 (2H, s), 3.81 (3H, s).

Part D. 3-(4-(Trifluoromethoxy)phenylthio)pyrazin-2(1H)-one

A solution of1-(4-methoxybenzyl)-3-(4-(trifluoromethoxy)phenylthio)-pyrazin-2(1H)-one(2.76 g, 6.76 mmol) in TFA (25 mL) was stirred at reflux for 2 days.Since LC-MS analysis revealed that 28% SM remained, the reaction wasstirred for 7 days. After removal of the TFA under vacuum, the crudeproduct was purified by silica gel chromatography employing a solventgradient (hexane to 100% EtOAc to elute3-(4-(trifluoromethoxy)phenylthio)pyrazin-2(1H)-one (1.60 g, 5.27 mmol,78% yield) as off-white solid. 1H NMR (400 MHz, chloroform-d) δ ppm 7.61(2H, d, J=9.03 Hz), 7.29 (2H, d, J=7.78 Hz), 7.24 (1H, d, J=4.02 Hz),7.07 (1H, d).

Part E.1-(4-(2-Hydroxy-2-methylpropoxy)-3-methylphenyl)-3-(4-(trifluoromethoxy)phenylthio)pyrazin-2(1H)-one

A mixture of 3-(4-(trifluoromethoxy)phenylthio)pyrazin-2(1H)-one (100mg, 0.347 mmol), 1-(4-bromo-2-methylphenoxy)-2-methylpropan-2-ol (90 mg,0.347 mmol), N1,N2-dimethylethane-1,2-diamine (92 mg, 1.041 mmol),copper(I) iodide (19.82 mg, 0.104 mmol) and K₃PO₄ (221 mg, 1.041 mmol)in dioxane (1.0 mL) was stirred at 115° C. in a sealed tube for 2 hours.After removal of the precipitate by filtration, the filtrate wasconcentrated. The crude product was purified by silica gelchromatography employing a solvent gradient (hexane to 100% EtOAc) toelute1-(4-(2-hydroxy-2-methylpropoxy)-3-methylphenyl)-3-(4-(trifluoromethoxy)phenylthio)-pyrazin-2(1H)-one(18.65 mg, 0.040 mmol, 11.52% yield) as off-white solid. 1H NMR (500MHz, methanol-d₃) δ ppm 7.62-7.68 (2H, m), 7.37 (2H, d, J=7.97 Hz),7.21-7.28 (3H, m), 7.16 (1H, d, J=4.40 Hz), 7.02 (1H, d, J=8.25 Hz),3.84 (2H, s), 2.31 (3H, s), 1.36 (6H, s).

Method 7 General Experimental Procedures for Preparation of3-(4-Chlorophenethoxy)-1-(4-(2-hydroxy-2-methylpropoxy)phenyl)pyrazin-2(1H)-one

Part A. 2-(4-Chlorophenethoxy)-3-methoxypyrazine

To a mixture of 2-(4-chlorophenyl)ethanol (1.246 g, 7.96 mmol) in THFwas added 1.0 M sodium bis(trimethylsilyl)amide in THF (6.92 mL, 6.92mmol). After stirring at RT under nitrogen for 18 hours, the reactionwas diluted with a solution of saturated NaHCO₃ (65 ml) and extractedwith EtOAc 720 ml). The ethyl acetate layer was dried over Na₂SO₄ andconcentrated. The crude product was purified by silica gelchromatography employing a solvent gradient (hexane to 30% ethylacetate) to elute 2-(4-chlorophenethoxy)-3-methoxypyrazine (1.25 g, 4.72mmol, 68.3% yield) as clear oil. 1H NMR (500 MHz, CDCl₃) δ ppm 7.61-7.64(1H, m), 7.59-7.61 (1H, m), 7.26-7.30 (2H, m), 7.20-7.24 (2H, m), 7.15(1H, d, J=8.52 Hz), 4.49-4.63 (2H, m), 4.02 (3H, s), 3.12 (2H, t, J=7.29Hz).

Part B. 3-(4-Chlorophenethoxy)pyrazin-2(1H)-one

A mixture of benzo[d]thiazole-2-thiol (1.264 g, 7.56 mmol),2-(4-chlorophenethoxy)-3-methoxypyrazine (1.00 g, 3.78 mmol) and NaHCO₃(1.587 g, 18.89 mmol) in DMA (10 mL) was stirred at 135° C. for 6 hours.After cooling to RT, the mixture was diluted with a solution ofsaturated NaHCO₃ (55 ml) and was then extracted with EtOAc (60 ml). TheEtOAc layer was dried over Na₂SO₄ and concentrated. The crude productwas purified by silica gel chromatography employing a solvent gradient(hexane to 100% EtOAc) to elute 3-(4-chlorophenethoxy)pyrazin-2(1H)-one(477 mg, 1.808 mmol, 47.9% yield) as off-white solid. 1H NMR (400 MHz,chloroform-d) δ ppm 7.27-7.31 (2H, m), 7.19-7.25 (2H, m), 6.95 (1H, d,J=4.27 Hz), 6.89 (1H, d, J=4.52 Hz), 4.54 (2H, t, J=7.53 Hz), 3.14 (2H,t, J=7.40 Hz).

Part C.3-(4-Chlorophenethoxy)-1-(4-(2-hydroxy-2-methylpropoxy)phenyl)pyrazin-2(1H)-one

A mixture of 3-(4-chlorophenethoxy)pyrazin-2(1H)-one (25 mg, 0.100mmol), K₃PO₄ (63.5 mg, 0.299 mmol), copper (1) iodide (18.99 mg, 0.100mmol), 1-(4-bromophenoxy)-2-methylpropan-2-ol andN,N′-dimethylethylenediamine (0.032 mL, 0.299 mmol) in dioxane (1.0 mL)was stirred at 110° C. for 60 min. After removal of the precipitate byfiltration, the filtrate was concentrated. The crude product waspurified by silica gel chromatography employing a solvent gradient(CH₂Cl₂ to 10% MeOH/CH₂Cl₂) to elute3-(4-chlorophenethoxy)-1-(4-(2-hydroxy-2-methylpropoxy)phenyl)pyrazin-2(1H)-one(31.82 mg, 0.073 mmol, 73.1% yield) as white solid. 1H NMR (500 MHz,chloroform-d) δ ppm 7.32 (2H, d), 7.23-7.29 (4 H, m), 7.02 (2H, d), 6.84(2H, s), 4.51 (2H, t, J=7.29 Hz), 3.83 (2H, s), 3.13 (2H, t, J=7.15 Hz),1.36 (6H, s).

TABLE 1 3-Thio substituted-1-arylpyrazin-2(1H)-ones

Ex. Aniline/Bromide No. Structure Component 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

HPLC Ex. Thiol Yield (Min) LC-MS H-NMR Data No. Component Method (%)Method 1 (M + H) (CDCl₃) 1

1 50 4.09 389/391 7.36(d, J = 8.4 Hz, 2H), 7.26(d, J = 8.4 Hz, 2H),7.41(d, J = 2.4 Hz, 1H), 7.25(d, J = 4.6 Hz, 1H), 6.98(d, J = 4.6 Hz,1H), 6.94(d, J = 2.2 Hz, 1H), 6.91(d, J = 8.5 Hz, 1H), 6.88(dd, J = 2.2and 8.5 Hz, 1H), 4.28(s, 2H), 3.91(s, 3H), 3.87(s, 3H). 2

1 4.60 435/437 7.44-7.24(m, 12H), 7.05(d, J = 8.9 Hz, 2H), 6.96(d, J =4.5 Hz, 1H), 5.09(s, 2H), 4.27(s, 2H). 3

1 9 4.23 403/405 7.27(m, 6H), 6.93(m ,3H), 3.92 (s, 3H), 3.89(s, 3H),3.30(t, J = 7.3 Hz, 2H), 2.98(t, J = 7.3 Hz, 2H) 4

1 68 4.01 369 7.28(m, 6H), 6.92(m, 4H), 3.91 (s, 3H), 3.88(s, 3H),3.32(dd, J = 2.2 and 7.5 Hz, 2H), 3.02(dd, J = 2.2 and 7.5 Hz, 2H) 5

2 11 2.36 370 CD₃OD) 8.35(dd, J = 1.0 and 4.5 Hz, 1H), 7.65(m, 1H),7.27(d, J = 7.8 Hz, 1H), 7.23(d, J = 4.3 Hz, 1H), 7.16(m, 1H), 7.11(d, J= 4.3 Hz, 1H), 6.93(d, J = 2.3 Hz, 1H), 6.92(d, J = 8.5 Hz, 1H),6.82(dd, J = 2.3 and 8.5 Hz, 1H), 3.74(s, 3H), 3.69(s, 3H), 3.33(t, J =7.1 Hz, 2H), 3.06(t, J = 7.1 Hz, 2H). 6

2 37 3.01 371 8.45(s, 1H), 8.44(d, J = 3.0 Hz, 1H), 8.33(d, J = 3.0 Hz,1H), 7.22(d, J = 4.5 Hz, 1H), 7.12(d, J = 4.5 Hz, 1H), 6.94(d, J = 2.4Hz, 1H), 6.93(d, J = 8.5 Hz, 1H), 6.83(dd, J = 2.4 and 8.5 Hz, 1H),374(s, 3H), 3.71(s, 3H), 3.39(t, J = 7.2 Hz, 2H), 3.13(t, J = 7.2 Hz,2H) 7

2 9 3.87 375/377 7.52(d, J = 8.5 Hz, 2H), 7.42(d, J = 8.5 Hz, 2H),7.13(d, J = 4.5 Hz, 1H), 6.97(d, J = 4.5 Hz, 1H), 6.95(m, 1H), 6.92(m,2H), 3.93(s, 3H), 3.99(s, 3H). 8

2 23 3.59 375/377 7.67(dd, J = 1.7 and 7.6 Hz, 1H), 7.57(dd, J = 1.3 and8.0 Hz, 1H), 7.43(dd, J = 1.7 and 7.6 Hz, 1H), 7.35 Hz(dd, J = 1.3 and7.5 Hz, 1H), 7.12(d, J = 4.4 Hz, 1H), 7.00 (d, J = 1.6 Hz, 1H), 6.98(d,J = 4.4 Hz, 1H), 6.95(m, 2H), 3.93(s, 3H), 3.91(s, 3H). 9

2 70 4.13 383 7.51(d, J = 8.2 Hz, 2H), 7.32(d, J = 8.2 Hz, 2H), 7.13(d,J = 4.5 Hz, 1H), 6.99(m, 1H), 6.96(d, J = 4.5 Hz, 1H), 6.91(m, 2H),3.92(s, 3H), 3.90(s, 3H), 2.96(sept, J = 7.7 Hz, 1H), 1.28(d, J = 7.7Hz, 6H). 10

2 60 4.02 425 7.61(d, J = 8.5 Hz, 2H), 7.29(d, J = 8.5 Hz, 2H), 7.13(d,J = 4.4 Hz, 1H), 7.00(d, J = 4.4 Hz, 1H), 6.96 (m, 1H), 6.92(m ,2H),3.93(s, 3H), 3.90(s, 3H) 11

1 2.5 3.94 433/435 7.36(m, 2H), 7.28(m, 3H), 6.96 (m, 3H), 6.87(m, 1H),4.72(s, 3H), 4.28(s, 2H), 2.87(s, 3H). 12

1 8 413 9.45(broad s, 1H), 7.39(m, 1H), 7.28(m, 5H), 6.98(m, 2H), 6.87(m, 2H), 4.73(s, 2H), 3.85(s, 3H), 3.34(t, J = 8.2 Hz, 2H), 3.01(t, J =8.2 Hz, 2H) 13 WSC, 27 3.95 466 7.30(m, H), 7.05(d, J = 7.5 Hz, HOBT1H), 7.01(d, J = 1.6 Hz, 1H), 6.96 medi- (d, J = 6.6 Hz, 1H), 6.84(dd, J= cated 1.6 and 7.5 Hz, 1H), 4.72(s, 2H), coupl- 3.87(s, 3H), 3.55(m,4H), 3.32(t, ing of J = 7.4 Hz, 2H), 3.02(t, J = 7.4 Ex 15 Hz, 2H),1.97(m, 2H) ,1.86(m, 2H). 14

4 3.9 3.96 419/421 7.36(m, 2H), 7.26(m, 3H), 6.97 (m, 3H), 6.87(m, 1H),4.28(s, 2H), 4.15(t, J = 4.2 Hz, 2H), 3.98 (t, J = 4.2 Hz, 2H), 3.85(s,3H). 15

2 Method 4 for ester hydrol- ysis 2 3.86 399 (CD₃OD) 7.41(d, J = 4.3 Hz,1H), 7.31(m, 4H), 7.26(d, J = 4.3 Hz, 1H), 7.20(m, 1H), 7.10(d, J = 8.6Hz, 1H), 7.12(d, J = 2.4 Hz, 1H), 7.00(dd, J = 2.4 and 8.6 Hz, 1H),4.09(t, J = 4.7 Hz, 2H), 3.92(s, 3H), 3.90(t, J = 4.7 Hz, 2H), 3.33 (dd,J = 6.0 and 8.0 Hz, 2H), 3.00 (dd, J = 6.0 and 8.0 Hz, 2H). 16

4 12 3.93 419/421 7.51(d, J = 8.5 Hz, 2H), 7.42(d, J = 8.5 Hz, 2H),7.13(d, J = 4.5 Hz, 1H), 6.99(m, 3H), 6.90(dd, J = 1.8 and 5.9 Hz, 1H),4.22(m, 1H), 4.04(dd, J = 3.0 and 9.5 Hz, 1H), 3.87(s, 3H), 3.84(dd, J =1.2 and 9.5 Hz, 1H), 2.77(broad s, 1H), 1.28(d, J = 6.4 Hz, 3H). 17

4 4.06 413 7.27(m, 6H), 6.97(m, 3H), 6.89 (dd, J = 2.2 and 8.4 Hz, 1H),4.23 (m, 1H), 4.03(dd, J = 3.0 and 9.6 Hz, 1H), 3.86(s, 3H), 3.84(dd, J= 1.0 and 9.6 Hz, 1H), 3.32(t, J = 5.4 Hz, 2H), 3.02(t, J = 5.4 Hz, 2H),2.83(broad s, 1H), 1.27(d, J = 6.4 Hz, 3H). 18

4 4.20 447/449 7.27(m, 5H), 6.98(m, 3H), 6.89 (dd, J = 2.4 and 8.5 Hz,1H), 4.23 (m, 1H), 4.02(dd, J = 3.0 and 9.6 Hz, 1H), 3.86(s, 3H),3.83(dd, J = 1.0 and 9.6 Hz, 1H), 3.30(t, J = 7.3 Hz, 2H), 2.98(t, J =7.3 Hz, 2H), 2.81(broad s, 1H), 1.27(d, J = 6.3 Hz, 3H). 19

4 4.13 427 7.23(m, 6H), 6.98(m, 2H), 6.97 (d, J = 4.6 Hz, 1H), 6.95(dd,J = 2.2 and 8.4 Hz, 1H), 4.23(m, 1H), 4.07(dd, J = 3.0 and 9.6 Hz, 1H),3.87(s, 3H), 3.84(dd, J = 1.0 and 9.6 Hz, 1H), 3.12(m, 2H), 2.81 (m,2H), 2.67(broad s, 1H), 2.07 (m, 2H), 1.27(d, J = 6.5 Hz, 3H). 20

4 2.45 414 8.57(d, J = 4.4 Hz, 1H), 7.62(dd, J = 1.6 and 6.5 Hz, 1H),7.27(m, 2H), 7.15(dd, J = 1.2 and 5.5 Hz, 1H), 6.96(m, 3H), 6.88(dd, J =2.4 and 8.5 Hz, 1H), 4.22(m, 1H), 4.02(dd, J = 3.0 and 9.5 Hz, 1H),3.85(s, 3H), 3.86(dd, J = 1.0 and 9.6 Hz, 1H), 3.50(t, J = 6.8 Hz, 2H),3.22(t, J = 6.8 Hz, 2H), 2.98 (broad s, 1H), 1.27(d, J = 8.6 Hz, 2H). 21MCPBA 57 3.18 435/437 7.96(d, J = 8.6 Hz, 2H), 7.65(d, oxida- J = 4.2Hz, 1H), 7.44(d, J = 8.6 tion of Hz, 2H), 7.35(d, J = 4.2 Hz, 1H), Ex 196.97(d, J = 8.5 Hz, 1H), 6.87(d, J = 2.1Hz, 1H), 6.84(dd, J = 2.1 and8.5 Hz, 1H), 4.23(m, 1H), 4.01(dd, J = 2.9 and 9.4 Hz, 1H), 3.85 (s,3H), 3.83(dd, J = 1.1 and 9.4 Hz, 1H) 1.27(d, J = 6.4 Hz, 3H). 22 MCPBA10 3.18 451/453 8.12(d, J = 8.6 Hz, 2H), 7.60(d, oxida- J = 6.1 Hz, 1H),7.51(d, J = 6.1 tion of Hz, 1H), 7.50(d, J = 8.6 Hz, 2H), Ex 19 6.96(d,J = 8.6 Hz, 1H), 6.90(d, J = 2.4 Hz, 1H), 6.84(dd, J = 2.4 and 8.6 Hz,1H), 4.23(m, 1H), 4.01(dd, J = 3.0 and 9.5 Hz, 1H), 3.86 (s, 3H),3.84(dd, J = 1.2 and 9.5 Hz, 1H) 1.28(d, J = 6.0 Hz, 3H). 23 MCPBA 172.96 445 7.52(d, J = 4.1 Hz, 1H), 7.40(d, oxida- J = 4.1 Hz, 1H), 7.20(m,5H), tion of 7.00(d, J = 8.6 Hz, 1H), 6.90(d, Ex 20 J = 2.5 Hz, 1H),6.81(dd, J = 2.5 and 8.6 Hz, 1H), 4.25(m, 1H), 4.05(dd, J = 3.1 and 9.5Hz, 1H), 3.88(s, 3H), 3.86(m, 3H), 3.20(t, H = 7.8 Hz, 2H), 1.29(d, J =6.2 Hz, 3H). 24 MCPBA 61 3.02 429 7.65(d, J = 6.2 Hz, 1H),7.30 oxida-(d, J = 6.2 Hz, 1H), 7.20(m, 5H), tion of 6.99(d, J = 8.4 Hz, 1H), 6.851.0 Ex 20 (d, J = Hz, 1H), 6.84(dd, J = 1.0 and 8.4 Hz, 1H) 4.25(m, 1H),4.02(dd, J = 2.9 and 9.6 Hz, 1H), 3.87(s, 3H), 3.85(dd, J = 1.2 and 9.6Hz, 1H), 3.61(m ,2H), 3.53(m, 1H), 3.17(m, 2H), 1.28(d, J = 6.8 Hz, 3H).25

2a 33 4.11 4.27 7.28(m, 2H), 6.97(d, J = 2.3 Hz, 1H), 6.97(d, J = 8.5Hz, 1H), 6.88 (dd, J = 2.3, 8.5 Hz, 1H), 3.86(s, 5H), 3.33(dd, J = 7.6and 8.8 Hz, 2H), 3.02(dd, J = 5.9 and 8.8 Hz, 2H), 1.36(s, 6H). 26

2a 10 3.8 445 7.25(d, J = 4.4 Hz, 1H), 7.17(m, 2H), 6.94(m, 5 H),6.84(dd, J = 2.2 and 8.5 Hz, 1H), 3.82(s, 3H), 3.77(s, 2H), 3.23(t, J =7.4 Hz, 2H), 2.91(t, J = 7.4 Hz, 2H), 1.27 (s, 6H) 27

2a 29 2.67 428 8.57(d, J = 4.2 Hz, 1H), 7.62(dd, J = 5.9 and 7.6 Hz,1H), 7.27(m, 2H), 7.15(m, 1H), 6.97(m, 3H), 6.88(dd, J = 2.3, 8.4 Hz,1H), 3.85 (s, 5H), 3.50(t, J = 7.2 Hz, 2H), 3.22(t, J = 7.2 Hz, 2H),1.36(s, 6H). 28

2a 31 2.74 428 8.68(d, J = 6.1 Hz, 2H), 797(d, J = 6.1 Hz, 2H), 7.29(d,J = 5.4 Hz, 1H), 7.21(d, J = 5.4 Hz, 1H), 7.00 (d, J = 2.0 Hz, 1H),6.98(d, J = 8.8 Hz, 1H), 6.86(dd, J = 2.0 and 8.8 Hz, 1H), 3.77(s, 3H),3.75(s, 2H), 3.42(t, J = 7.2 Hz, 2H), 3.30(t, J = 7.2 Hz, 2H), 1.24(s,6H). 29

2a 12 4.02 518 8.94(d, J = 4.5 Hz, 1H), 8.36(d, J = 8.8 Hz, 1H), 8.32(s,1H), 7.92 (d, J = 4.5 Hz, 1H), 7.74(dd, J = 1.5 and 8.9 Hz, 1H), 7.21(d,J = 4.4 Hz, 1H) ,7.06(d, J = 2.3 Hz, 1H), 7.00(d, J = 8.6 Hz, 1H), 6.92(dd, J = 2.3 and 8.6 Hz, 1H), 6.90 (d, J = 4.4 Hz, 1H), 3.79(s, 3H),3.75(s, 2H), 1.24(s, 6H). 30

2a 50 3.76 433/435 7.67(dd, J = 1.4 and 7.5 Hz, 1H), 7.56(dd, J = 1.2and 8.0 Hz, 1H), 7.42(dt, J = 1.4 and 7.5 Hz, 1H), 7.36(dt, J = 1.2 and7.5 Hz, 1H), 7.11(d, J = 4.5 Hz, 1H), 7.01(d, J = 2.3 Hz, 1H), 6.96(d, J= 8.4 Hz, 1H), 6.93(d, J = 4.5 Hz, 1H), 6.90 (dd, J = 2.3 and 8.4 Hz,1H), 3.87 (s, 3H), 3.86(s, 2H), 2.72(broad s, 1H), 1.36(s, 6H). 31

2a 62 3.98 433/435 7.59(d, J = 1.7 Hz, 1H), 7.48(m, 1H), 7.41(m, 2H),7.14(d, J = 4.5 Hz, 1H), 7.00(m, 3H), 6.90(dd, J = 2.4 and 8.5 Hz, 1H),3.87(s, 3H), 3.86(s, 2H), 2.71(broad s, 1H), 1.36(s, 6H). 32

2a 58 4.00 433/435 7.52(dd, J = 1.9 and 6.7 Hz, 2H), 7.43(dd, J = 1.9and 6.7 Hz, 2H), 7.13(d, J = 4.4 Hz, 1H), 6.99(d, J = 2.3 Hz, 1H),6.98(d, J = 4.4 Hz, 1H), 6.96(d, J = 8.4 Hz, 1H), 6.90 (dd, J = 2.3 and8.4 Hz, 1H), 3.87 (s, 3H), 3.86(s, 2H), 2.70(broad s, 1H), 1.36(s, 6H).33

2a 70 4.11 449 8.12(s, 1H), 7.88(m, 3H), 7.61 (dd, J = 1.4 and 8.6 Hz,1H), 7.53 (m, 2H), 7.09(d, J = 4.5 Hz, 1H), 7.02(d, J = 2.3 Hz, 1H),6.98(d, J = 8.5 Hz, 1H), 6.96(d, J = 4.5 Hz, 1H), 6.91(dd, J = 2.3 and8.5 Hz, 1H), 3.88(s, 3H), 3.87(s, 2H), 2.75(broad s, 1H), 1.37(s, 6H).34

2a 34 3.72 417 7.56(m, 2H), 7.12(m, 3H), 6.98 (m, 3H), 6.89(m, 1H),3.86(s, 5H), 1.36(s, 6H). 35

2a 39 4.24 441 7.50(d, J = 8.2 Hz, 2H), 7.32(d, J = 8.2 Hz, 2H), 7.15(d,J = 4.5 Hz, 1H), 7.02(d, J = 2.3 Hz, 1H), 6.97 (d, J = 4.5 Hz, 1H),6.96(d, J = 8.5 Hz, 1H), 6.92(dd, J = 2.3 and 8.5 Hz, 1H), 3.90(s, 3H),3.85(s, 2H), 2.98(m, 1H), 2.85(broad s, 1H), 1.35(s, 6H), 1.24(d, J =6.8 Hz, 6H). 36

2a 16 4.10 467 7.64(d, J = 9.0 Hz, 2H), 7.62(d, J = 9.0 Hz, 2H), 7.18(d,J = 4.5 Hz, 1H), 7.04(d, J = 4.5 Hz, 1H), 7.00 (d, J = 2.2 Hz, 1H),6.98(d, J = 8.5 Hz, 1H), 6.86(dd, J = 2.2 and 8.5 Hz, 1H), 3.75(s, 1H),3.73(s, 2H), 1.22(s, 6H). 37

2a 50 3.96 445 7.48(d, J = 8.4 Hz, 2H), 7.30(d, J = 8.4 Hz, 2H), 7.28(d,J = 4.5 Hz, 1H), 7.12(d, J = 4.5 Hz, 1H), 6.99 (d, J = 8.5 Hz, 1H),6.96(d, J = 2.4 Hz, 1H), 6.89(dd, J = 2.4 and 8.5 Hz, 1H), 3.86(s, 5H),2.51(s, 3H), 1.35(s, 6H). 38

2a 52 415 483 7.62(d, J = 8.6 Hz, 2H), 7.30(d, J = 8.6 Hz, 2H), 7.16(d,J = 4.4 Hz, 1H), 7.06(d, J = 4.4 Hz, 1H), 7.00 (d, J = 8.5 Hz, 1H),6.98(d, J = 2.3 Hz, 1H), 6.95(dd, J = 2.3 and 8.5 Hz, 1H), 3.91(s, 3H),3.86(s, 2H), 1.36(s, 6H). 39

2a 60 3.72 429 7.37(t, J = 8.0 Hz, 1H), 7.18(d, J = 8.0 Hz, 1H), 7.14(m,2H), 6.98 (m, 4H), 6.90(m, 1H), 3.86(s, 5H), 3.77(s, 3H), 1.36(s, 6H).40

2a 49 3.88 467 7.84(d, J = 7.5 Hz, 1H), 7.71(d, J = 7.5 Hz, 1H), 7.62(t,J = 7.5 Hz, 1H), 7.60(t, J = 7.5 Hz, 1H), 7.05 (d, J = 4.4 Hz, 1H),7.01(d, J = 2.4 Hz, 1H), 6.98(d, J = 8.5 Hz, 1H), 6.97(d, J = 4.4 Hz,1H), 6.90(dd, J = 2.4 and 8.5 Hz, 1H), 3.88(s, 3H), 3.86(s, 2H), 1.36(s,6H). 41

2a 50 4.20 447/449 7.48(d, J = 8.4 Hz, 1H), 7.36(d, J = 2.0 Hz, 1H),7.24(dd, J = 2.0 and 8.4 Hz, 1H), 7.10(d, J = 4.5 Hz, 1H), 7.00(d, J =2.4 Hz, 1H), 6.98(d, J = 8.5 Hz, 1H), 6.96(d, J = 4.5 Hz, 1H), 6.90(dd,J = 2.4 and 8.5 Hz, 1H), 3.88(s, 3H), 3.87 (s, 2H), 2.40(s, 3H), 1.38(s,6H). 42

2a 60 4.04 427 7.44(d, J = 7.9 Hz, 1H), 7.19(s, 1H), 7.11(d, J = 4.5 Hz,1H), 7.08 (d, J = 7.9 Hz, 1H), 7.01(d, J = 2.3 Hz, 1H), 6.97(d, J = 8.6Hz, 1H), 6.93(d, J = 4.5 Hz, 1H), 6.90(dd, J = 2.3 and 8.6 Hz, 1H),3.87(s, 3H), 3.86(s, 2H), 2.39(s, 3H), 2.37(s, 3H), 1.36(s, 6H). 43

2a 60 3.87 413 7.46(d, J = 8.0 Hz, 2H), 7.27(d, J = 8.0 Hz, 2H), 7.15(d,J = 4.4 Hz, 1H), 7.01(d, J = 2.3 Hz, 1H), 6.97 (d, J = 8.5 Hz, 1H),6.96(d, J = 4.4 Hz, 1H), 6.92(dd, J = 2.3 and 8.5 Hz, 1H), 3.91(s, 3H),3.85(s, 2H), 2.40(s, 3H), 1.35(s, 6H). 44

2a 39 3.71 429 7.48(d, J = 8.7 Hz, 2H), 7.14(d, J = 4.5 Hz, 1H), 7.00(d,J = 2.3 Hz, 1H), 6.99(d, J = 8.0 Hz, 2H), 6.97 (d, J = 4.5 Hz, 1H),6.97(d, J = 8.5 Hz, 1H0, 6.92(dd, J = 2.3 and 8.5 Hz, 1), 3.89(s, 3H),3.85(s, 5H), 1.35(s, 6H). 45

2a 64 4.05 427 7.45(d, J = 8.3 Hz, 2H), 7.25(d, J = 8.3 Hz, 2H), 7.11(d,J = 3.9 Hz, 1H), 6.97(d, J = 2.2 Hz, 1H), 6.93 (d, J = 8.2 Hz, 1H),6.92(d, J = 3.9 Hz, 1H), 6.87(dd, J = 2.2 and 8.2 Hz, 1H), 3.86(s, 3H),3.81(s, 2H), 2.66(q, J = 5.5 Hz, 2H), 1.31(s, 6H), 1.22(t, J = 5.5 Hz,3H). 46

2a 29 4.25 441 7.27(m, 5H), 7.20(m, 1H), 6.92 (m, 3H), 6.85(dd, J = 2.28.0 Hz, 1H), 3.97(m, 1H), 3.84(s, 3H), 3.81(s, 2H), 3.16(dd, J = 2.0 and8.0 Hz, 1H), 2.74(dd, J = 5.0 and 8.0 Hz, 1H), 1.33(s, 6H), 1.32(d, J =9.3 Hz, 3H). 47

2a 59 4.31 441 7.30(m, 1H), 7.21(m, 1H), 7.11 (m, 1H), 7.05(m, 1H),6.97(m, 4H), 6.89(m, 1H), 3.87(s, 3H), 3.84(s, 2H), 3.31(dd, J = 6.0 and8.3 Hz, 2H), 2.98(t, J = 8.3 Hz, 2H), 2.35(s, 3H), 1.35(s, 6H) 48

2a 88 4.30 441 7.26(d, J = 4.4 Hz, 1H), 7.39(d, J =7.2 Hz, 1H), 7.10(m,3H), 6.95(m, 3H), 6.84(dd, J = 2.2 and 8.2 Hz, 1H), 3.83(s, 3H), 3.79(s,2H), 3.22(dd, J = 5.7 and 8.5 Hz, 2H), 2.96(dd, J = 5.5 and 8.5 Hz, 2H),2.34(s, 3h), 1.29(s, 6H). 49

2a 51 3.62 399 7.52(m, 2H), 7.39(m, 3H), 7.05 (d, J = 4.4 Hz, 1H),6.92(d, J = 2.4 Hz, 1H), 6.90(d, J = 8.4 Hz, 1H), 6.89(d, J = 4.4 Hz,1H), 6.83(dd, J = 2.4 and 8.4 Hz, 1H), 3.80(s, 3H), 3.79(s, 2H), 1.29(s,6H). 50

2a 51 3.95 413 7.43(d, J = 7.1 Hz, 2H), 7.30(m, 4H), 6.96(m, 3H),6.88(dd, J = 2.4 and 8.5 Hz, 1H), 4.33(s, 2H), 3.87(s, 3h), 3.84(s, 2H),1.35(s, 6H). 51

2a 6 3.63 468 8.89(s, 1H), 8.17(d, J = 7.2 Hz, 1H), 8.10(d, J = 7.2 Hz,1H), 7.45 (d, J = 4.4 Hz, 1H), 7.30(d, J = 4.4 Hz, 1H), 7.15(d, J = 2.4Hz, 1H), 7.12(d, J = 8.6 Hz, 1H), 7.01(dd, J = 2.4 and 8.6 Hz, 1H),3.91(s, 3H), 3.87(s, 2H), 1.35(s, 6H). 52

2a 50 4.02 433/435 7.67(dd, J = 1.4 and 7.5 Hz, 1H), 7.56(dd, J = 1.2and 8.0 Hz, 1H), 7.42(dt, J = 1.4 and 7.5 Hz, 1H), 7.36(dt, J = 1.2 and7.5 Hz, 1H), 7.11(d, J = 4.5 Hz, 1H), 7.01(d, J = 2.3 Hz, 1H), 6.96(d, J= 8.4 Hz, 1H), 6.93(d, J = 4.5 Hz, 1H), 6.90 (dd, J = 2.3 and 8.5 Hz,1H), 3.87 (s,3H), 3.96(s, 2H), 2.72(broad s, 1H), 1.36(s, 6H). 53

2a 62 3.76 433/435 7.59(d, J = 1.7 Hz, 1H), 7.48(m, 1H), 7.41(m, 2H),7.14(d, J = 4.5 Hz, 1H), 7.00(m, 3H), 6.90(dd, J = 2.4 and 8.5 Hz, 1H),3.87(s, 3H), 3.86(s, 2H), 2.71(broad s, 1H), 1.36(s, 6H). 54

2a 58 3.98 433/435 7.52(dd, J = 1.9 and 6.7 Hz, 2H), 7.43(dd, J = 1.9and 6.7 Hz, 2H), 7.13(d, J = 4.4 Hz, 1H), 6.99(d, J = 2.3 Hz, 1H),6.98(d, J = 4.4 Hz, 1H), 6.96(d, J = 8.4 Hz, 1H), 6.90 (dd, J = 2.3 and8.4 Hz, 1H), 3.87 (s, 3H), 3.86(s, 2H), 2.70(broad s, 1H), 1.36(s, 6H).55

2a 50% 2.74 442 7.67(t, J = 7.7 Hz, 1H), 7.38(d, J = 4.4 Hz, 1H),7.25(d, J = 4.4 Hz, 1H), 7.16(m, 2H), 7.10(d, J = 2.4 Hz, 1H), 7.08(d, J= 8.6 Hz, 1H), 6.95(dd, J = 2.4 and 8.6 Hz, 1H), 3.89(s, 3H), 3.86(s,2H), 3.45(t, J = 7.1 Hz, 2H), 3.15(t, J = 7.1 Hz, 2H), 2.53(s, 3H),1.34(s, 6H). 56

2a 44% 3.03 442 7.40(d, J = 8.9 Hz, 2H), 7.13(d, J = 4.8 Hz, 1h),7.00(d, J = 2.3 Hz, 1H), 6.97(d, J = 8.5 Hz, 1H), 6.92 (d, J = 4.8 Hz,1H), 6.90(dd, J = 2.3 and 8.5 Hz, 1H), 6.76(d, J = 8.9 Hz, 2H), 3.87(s,3H), 3.86(s, 2H), 3.01(s, 6H), 1.36(s, 6H). 57

5 3 3.68 486 7.77(d, J = 8.8 Hz, 1H), 7.57(d, J = 2.5 Hz, 1H), 7.37(d, J= 4.4 Hz, 1H), 7.14(d, J = 4.4 Hz, 1H), 7.08 (dd, J = 2.5, 8.8 Hz, 1H),7.02(m, 2H), 6.93(dd, J = 2.5, 8.5 Hz, 1H), 3.92(s, 3H), 3.90(s, 2H),1.39(s, 6H). 58

5 3.64 456 7.93(d, J = 8.3 Hz, 1H), 7.87(d, J = 8.1 Hz, 1H), 7.43(t, J =8.2 Hz, 1H), 7.35(m, 3H), 7.07(d, J = 2.3 Hz, 1H), 7.01(d, J = 8.6 Hz,1H), 6.93(dd, J = 2.3 and 8.5 Hz, 1H), 3.79(s, 3H), 3.76(s, 2H), 1.24(s,6H). 59

5 3.99 490/492 7.87(d, J = 8.6 Hz, 1H), 7.79(d, J = 2.0 Hz, 1H),7.38(dd, J = 2.0 and 8.6 Hz, 1H), 7.30(d, J = 4.4 Hz, 1H), 7.08(d, J =4.4 Hz, 1H), 6.92(d, J = 2.5 Hz, 1H), 6.91(d, J = 8.6 Hz, 1H), 6.85(dd,J = 2.5 and 8.6 Hz, 1H), 3.80(s, 5H), 1.30(s, 6H). 60

5 3.67 474/476 7.71(d, J = 2.0, 1H), 7.45(d, J = 8.7 Hz, 1H), 7.32(dd, J= 2.0 and 8.7 Hz, 1H), 7.11(d, J = 4.4 Hz, 1H), 7.04(d, J = 4.4 Hz, 1H),6.91 (d, J = 8.6 Hz, 1H), 6.90(d, J = 2.4 Hz, 1H), 6.84(dd, J = 2.4 and8.6 Hz, 1H), 3.81(s, 3H), 3.79(s, 2H), 1.29(s, 6H). 61

5 2.68 439 7.71(dd, J = 3.1 and 6.2 Hz, 2H), 7.49(dd, J = 3.1 and 6.2Hz, 2H), 7.43(d, J = 4.4 Hz, 1H), 7.22(d, J = 4.4 Hz, 1H), 7.04(d, J =2.5 Hz, 1H), 7.01(d, J = 8.5 Hz, 1H), 6.91 (dd, J = 2.4 and 8.5 Hz, 1H),3.79 (s, 3H), 3.75(s, 2H), 1.24(s, 6H). 62

5 4.11 484 7.68(d, J = 8.8 Hz, 1H), 7.46(d, J = 2.4 Hz, 1H), 7.27(d, J =4.4 Hz, 1H), 7.16(m, 2H), 7.04(d, J = 4.4 Hz, 1H), 7.00(dd, J = 2.5 and8.7 Hz, 1H), 6.85(d, J = 9.4 Hz, 1H), 3.82(s, 3H), 3.78(s, 2H), 2.65(q,J = 7.5 Hz, 2H), 1.32(s, 6H), 1.15 (t, J = 7.5 Hz, 3H). 63

2a 4.05 465 7.64(d, J = 8.5 Hz, 2H), 7.62(d, J = 8.5 Hz, 2H), 7.15(m,2H), 7.04 (d, J = 4.4 Hz, 1H), 6.93(d, J = 4.4 Hz, 1H), 6.84(d, J = 9.2Hz, 1H), 3.77(s, 2H), 2.63(q, J = 7.5 Hz, 2H), 1.30(s, 6H), 1.17(t, J =7.5 Hz, 3H) 64

2a 4.15 481 7.43(d, J = 8.8 Hz, 2H), 7.31(d, J = 8.8 Hz, 2H), 7.24(d, J= 2.4 Hz, 1H), 7.22(d, J = 8.5 Hz, 1H), 7.14(d, J = 4.4 Hz, 1H), 7.00(d,J = 4.4 Hz, 1H), 6.94(dd, J = 2.4, 8.5 Hz, 1H), 3.86(s, 2H), 2.74(q, J =7.5 Hz, 2H), 1.41(s, 6H), 1.26(t, J = 7.5 Hz, 3H). 65

2a 4.08 Method 2 425 7.10(m, 8H), 6.84(d, J = 4.4 Hz, 1H), 6.76(d, J =8.5 Hz, 1H), 3.70 (s, 2H), 3.21(m, 2H), 2.90(m, 2H), 2.59(q, J = 7.4 Hz,2H), 1.26 (s, 6H), 1.12(t, J = 7.4 Hz, 3H) 66

2a 3.81 439 7.23(m, 5H), 7.14(m, 1H), 6.92 (m, 3H), 6.83(dd, J = 2.4,8.6 Hz), 4.08(dd, J = 2.6, 9.7 Hz, 1H), 3.93(t, J = 8.2 Hz, 1H), 3.80(s,3H), 3.25(m, 3H), 2.94(m, 2H), 0.88 (m, 1H), 0.57(m, 1H), 0.51(m, 1H),0.36(m, 1H), 0.22(m, 1H) 67

2a 3.87 495 7.54(d, J = 8.8 Hz, 2H), 7.21(d, J = 8.8 Hz, 2H), 7.05(d, J= 4.4 Hz, 1H), 6.93(d, J = 8.5 Hz, 1H), 6.92 (d, J = 2.4 Hz, 1H),6.91(d, J = 4.4 Hz, 1H), 6.84(dd, J = 2.4, 8.5 Hz, 1H), 4.13(dd, J =2.8, 9.7 Hz, 1H), 3.96(dd, J = 1.3, 8.2 Hz, 1H), 3.79(s, 3H), 3.29(dt, J= 2.5, 9.8 Hz, 1H), 0.93(m, 1H), 0.57(m, 1H), 0.51(m, 1H), 0.41(m, 1H),0.25(m, 1H) 68

2a 3.74 Method 2 479 7.66(d, J = 8.5 Hz, 2H), 7.64(d, J = 8.5 Hz, 2H),7.51(d, J = 4.4 Hz, 1H), 7.09(d, J = 4.4 Hz, 1H), 7.00(d, J = 8.2 Hz,1H), 6.98(d, J =2.2 Hz, 1H), 6.89(dd, J = 2.2, 8.2 Hz,1H), 4.22(dd, J =2.2, 9.3 Hz, 1H), 3.96(dd, J = 1.1, 9.4 Hz, 1H), 3.84(s, 3H), 3.27(dt, J= 2.5, 9.8 Hz, 1H), 0.93(m, 1H), 0.57(m, 1H), 0.51(m, 1H), 0.41(m, 1H),0.25 (m, 1H) 69

2a 3.59 Method 2 481 7.64(m, 4H), 7.06(d, J = 4.4 Hz, 1H), 6.98(d, J =2.8 Hz, 1H), 6.95 (d, J = 9.7 Hz, 1H), 6.93(d, J = 4.4 Hz, 1H), 6.86(dd,J = 2.8 and 9.7 Hz, 1H), 4.63(m, 1H), 4.34(m, 1H), 4.09(m, 1H), 3.97(m,2H), 3.83(s, 3H), 3.78(m, 1H), 3.07(d, J = 6.4 Hz, 1H). 70

2a 3.87 Method 2 479 7.62(m, 4 H), 7.05(d, J = 4.5 Hz, 1H), 6.95(d, J =8.5 Hz, 1H), 6.93 (d, J = 4.5 Hz, 1H), 6.92(d, J = 2.4 Hz, 1H), 6.83(dd,J = 2.4 and 8.5 Hz, 1H), 4.42(m, 1H), 4.13(m, 1H), 3.75(s, 3H), 3.04(m,1H), 1.99(m, 1H), 1.70 to 1.90(m, 4H), 1.52(m, 1H). 71

2a 3.74 Method 2 453 7.85(d, J = 8.4 Hz, 2H), 7.80(d, J = 8.4 Hz, 2H),7.48(d, J = 4.4 Hz, 1H), 7.16(d, J = 4.4 Hz, 1H), 7.15 (d, J = 2.4 Hz,1H), 7.10(d, J = 8.6 Hz, 1H), 7.01(dd, J = 2.4, 8.6 Hz, 1H), 3.97(m,1H), 3.90(m, 1H), 3.81(m, 1H), 3.78(s, 3H), 1.16(d, 3H) 72

2a 3.72 Method 2 483 7.64(m, 4H), 7.06(d, J = 4.5 Hz, 1H), 6.96(d, J =8.5 Hz, 1H), 6.94 (d, J = 4.5 Hz, 1H), 6.92(d, J = 2.5 Hz, 1H), 6.84(dd,J = 2.5, 8.5 Hz, 1H), 4.04(m, 2H), 3.81(s, 3H), 3.50(m, 2H), 3.36(s, 3H)73

2a 3.62 Method 7 545 7.63(m, 4H), 7.06(d, J = 4.4 Hz, 2H), 6.94(d, J =4.4 Hz, 1H), 6.92 (d, J = 2.0 Hz, 1H), 6.90(d, J = 8.5 Hz, 1H), 6.83(dd,J = 2.0 and 8.5 Hz, 1H), 4.54(m, 1H), 4.02(d, J = 5.4 Hz, 2H), 3.78(s,3H), 3.62(m, 1 H), 3.0 to 3.40(m, 3H), 1.86(m, 1 H), 1.38(t, J = 7.4 Hz,3H). 74

2a 507 3.90(s, 3H), 4.14-4.22(m, 1H), 4.32(dd, J = 10.45, 3.65 Hz, 1H),4.36-4.47(m, 1H), 7.03(dd, J = 8.56, 2.27 Hz, 1H), 7.14-7.22 (m, 3H),7.34(d, J = 4.28 Hz, 1H), 7.74-7.83(m, 4H) 75

2a 531 ¹H NMR (400 MHz, MeOD) δ ppm 7.69(d, 2H), 7.38(d, 2H), 7.33(d,1H), 7.18(m, 3H), 7.03(d, 1H), 4.09(s, 2H), 3.91(s, 3H), 2.93(m, 2H),2.66(m, 2H). 76

2a 515 ¹H NMR (400 MHz, MeOD) δ ppm 7.78(s, 4H), 7.34(s, 1H), 7.19(m,3H), 7.03(d, 1H), 4.09(s, 2H), 3.90(s, 3H), 2.93₋m, 2H), 2.66(m, 2H). 77

2a 474 ¹H NMR (400 MHz, MeOD) δ ppm 7.78(d, 1H), 7.53(m, 3H), 7.30(m,1H), 7.20(s, 1H), 7.12(m, 1H), 7.06(d, 1H), 3.91(s, 3H), 3.88(s, 2H),1.36(s, 6H). 78

2a 474 ¹H NMR (400 MHz, MeOD) δ ppm 7.85(d, 1H), 7.53(m, 3H), 7.21(m,4H), 3.91(s, 3H), 3.88(s, 2H), 1.36(s, 6H). 79

2a 474 ¹H NMR (400 MHz, MeOD) δ ppm 7.97(d, 1H), 7.85(d, 1H), 7.53(d,2H), 7.35(t, 1H), 7.21(s, 1H), 7.16(m, 1H), 7.07(m, 1H), 3.91(s, 1H),3.88(s, 2H), 1.36(s, 6H). 80

6 479 ¹H NMR (400 MHz, MeOD) δ ppm 7.68(d, 2H), 7.40(d, 2H), 7.28(s,1H), 7.17(m, 1H), 6.97(d, 1H), 3.82(s, 1H), 2.96(m, 2H), 2.24(m, 1H),2.81(m, 1H), 1.33(s, 6H). 81

6 491 ¹H NMR (400 MHz, MeOD) δ ppm 7.69(d, 2H), 7.40(d, 2H), 7.28(m,2H), 7.20(m, 2H), 6.91(d, 1H), 5.79(s, 1H), 4.70(s, 1H), 2.08(s, 2H),1.31(d, 6H). 82

6 495 ¹H NMR (400 MHz, CDCl₃) δ ppm 7.61(d, 2H), 7.59(s, 1H), 7.28(m,2H), 7.14(m, 2H), 6.99(s, 1H), 6.92(d, 1H), 4.87(t, 1H), 4.00(d, 1H),2.36(m, 1H), 1.84(q, 1H), 1.38(d, 6H). 83

6 433 (M + H - H₂O) ¹H NMR (400 MHz, MeOD) δ ppm 7.70(d, 2H), 7.61(s,1H), 7.43(d, 2H), 7.28(m, 2H), 7.20(s, 1H), 6.95(d, 1H), 4.35(m, 2H),2.12(br-s, 2H), 1.62(s, 3H). 84

6 453 ¹H NMR (500 MHz, chloroform- d) δ ppm 7.62(2 H, d, J = 8.80 Hz),7.36(2 H, d, J = 8.80 Hz), 7.29(2 H, d, J = 7.97 Hz), 7.13(1 H, d, J =4.67 Hz), 7.04(2 H, d, J = 8.80 Hz), 6.98(1 H, d, J = 4.40 Hz), 3.84(2H, s), 1.37(6 H, s). 85

6 449 ¹H NMR (500 MHz, chloroform- d) δ ppm 8.31(1 H, dd, J = 6.19, 3.44Hz), 8.00(1 H, d, J = 8.25 Hz), 7.85-7.95(2 H, m), 7.51-7.56(3 H, m),7.04(1 H, d, J = 2.20 Hz), 6.97-7.02(1 H, m), 6.89-6.96(3 H, m), 3.90(3H, s), 3.88(2 H, s), 1.37(6 H, s). 86

6 471 ¹H NMR (500 MHz, methanol-d₃) δ ppm 7.62-7.68(2 H, m), 7.34-7.39(3 H, m), 7.21-7.29(3 H, m), 7.15(1 H, d, J = 4.40 Hz), 3.91 (2 H,s), 1.34(6 H, s). 87

6 467 ¹H NMR (500 MHz, methanol-d₃) δ ppm 7.62-7.69(2 H, m), 7.36(2 H,d, J = 7.97 Hz), 7.21-7.28(3 H, m), 7.15(1 H, d, J = 4.40 Hz), 7.02(1 H,d, J = 8.52 Hz), 3.84(2 H, s), 2.31(3 H, s), 1.36(6 H, s). 88

6 487 ¹H NMR (500 MHz, methanol- d₃) δ ppm 7.65(2 H, d, J = 8.80 Hz),7.59(1 H, d, J = 2.75 Hz), 7.33-7.41(3 H, m), 7.27(1 H, d, J = 4.40 Hz),7.22(1 H, d, J = 8.80 Hz), 7.15(1 H, d, J = 4.40 Hz), 3.91(2 H, s),1.37(6 H, s) 89

6 537 ¹H NMR (500 MHz, methanol-d₃) δ ppm 7.66(2 H, d), 7.52-7.56(1H,m), 7.46(1 H, dd, J = 8.94, 2.61 Hz), 7.37(2 H, d, J = 7.97 Hz), 7.33 (1H, d, J = 8.80 Hz), 7.29(1 H, d, J = 4.40 Hz), 7.16(1 H, d, J = 4.67Hz), 3.91(2 H, s), 1.34(6 H, s). 90

6 478 ¹H NMR (500 MHz, methanol-d₃) δ ppm 7.85(1 H, d, J = 2.75 Hz),7.74(1 H, dd, J = 8.94, 2.61 Hz), 7.65(2 H, d), 7.33-7.39(3 H, m),7.29(1 H, d, J = 4.67 Hz), 7.16(1 H, d, J = 4.40 Hz), 4.01(2 H, s),1.38(6 H, s). 91

6 489 ¹H NMR (500 MHz, methanol-d₃) δ ppm 7.65(2 H, d, J = 8.80 Hz),7.37 (2 H, d, J = 7.97 Hz), 7.24-7.32 (3 H, m), 7.15(1 H, d, J = 1.40Hz), 4.00(2 H, s), 1.33(6 H, s). 92

6 501 1H NMR (500 MHz, methanol-d₃) δ ppm 7.65(2 H, d, J = 8.80 Hz),7.45(1 H, d, J = 2.75 Hz), 7.37(2 H, d, J = 7.97 Hz), 7.30(1 H, d, J =1.92 Hz), 7.27(1 H, d, J = 4.40 Hz), 7.15(1 H, d, J = 4.67 Hz), 3.78(2H, s), 2.40(3 H, s), 1.39(6 H, s). 93

6 521 1H NMR (500 MHz, methanol-d₃) δ ppm 7.77 (1 H, d, J = 2.47 Hz),7.62- 7.71(3 H, m), 7.35(3 H, dd, J = 14.57, 8.52 Hz), 7.30(1 H, d, J =4.40 Hz), 7.17(1 H, d, J = 4.40 Hz), 3.94(2 H, s), 1.35(6 H ,s). 94

6 505 1H NMR (500 MHz, methanol-d₃) δ ppm 7.65(2 H, d), 7.46-7.51(1H,m), 7.42(1 H, dd, J = 11.27, 2.47 Hz), 7.37(2 H, d, J = 7.97 Hz), 7.28(1 H, d, J = 4.40 Hz), 7.15(1 H, d, J = 4.40 Hz), 3.98(2 H, s), 1.37(6H, s). 95

6 452 1H NMR (500 MHz, chloroform-d) δ ppm 8.88(1 H, s), 7.89-7.99 (2 H,m), 7.16-7.24(3 H, m), 7.07(1 H, d, J = 4.40 Hz), 6.90(1 H, d, J = 8.52Hz), 3.84(2 H, s), 2.30(3 H, s), 1.39(6 H, s). 96

6 481 1H NMR (500 MHz, chloroform- d) δ ppm 7.62(2 H, d, J = 8.78 Hz),7.29(2 H, d, J = 8.03 Hz), 7.11(1 H, d, J = 4.52 Hz), 7.08(2 H, s),6.96(1 H, d, J = 4.52 Hz), 3.64(2 H, s), 2.33(6 H, s), 1.39(6 H, s). 97

6 477 1H NMR (400 MHz, MeOD) δ ppm 7.68(d, 2H), 7.39(d, 2H), 7.28(d,1H), 7.18(m, 3H), 6.93(d, 1H), 6.49(s, 1H), 1.42(s, 6H). 98

6 481 1H NMR (400 MHz, MeOD) δ ppm 7.69(2 H, d), 7.39(2 H, d, J = 8.03Hz), 7.18(2 H, dd), 7.08 (1 H, d, J = 8.53 Hz), 6.93(1 H, d, J = 8.78Hz), 3.84(2 H, s), 2.30(3 H, s), 2.02(3 H, s), 1.38(6 H, s). 99

6 441 1H NMR (500 MHz, chloroform- d) δ ppm 7.23-7.31(2 H, m),7.16-7.23(2 H, m), 7.07(1 H, d, J = 7.42 Hz), 6.98-7.04(1 H, m),6.88-6.98(23 H, m), 4.14(1 H, dd, J = 9.35, 3.30 Hz), 4.04(1 H, dd, J =9.35, 7.15 Hz), 3.26-3.40(3 H, m), 2.97-3.06(2 H, m), 2.27(3 H, s),0.99-1.10(1 H, m), 0.55- 0.68(2 H, m), 0.43-0.51(1 H, m), 0.30-0.38(1 H,m) 100

6 481 1H NMR (400 MHz, chloroform- d) δ ppm 7.63(2 H, dd, J = 8.78, 2.26Hz), 7.30(2 H, d, J = 7.78 Hz), 7.11(1 H, dd, J = 4.27, 2.26 Hz), 6.98(1H, s), 6.84(1 H, dd, J = 4.52, 2.26 Hz), 6.76(1 H, s), 3.84(2 H, br.s.), 2.24(3 H, s), 2.14(3 H, s), 1.39(6 H, d, J = 2.26 Hz). 101

6 437 1H NMR (500 MHz, chloroform- d) δ ppm 7.71(4 H, m), 7.36(2 H, d, J= 8.80 Hz), 7.13(1 H, d, J = 4.40 Hz), 7.04(2 H, d, J = 9.35 Hz), 7.00(1H, d, J = 4.40 Hz), 3.84(2 H, s), 1.37(6 H, s). 102

6 455 1H NMR (500 MHz, chloroform- d) δ ppm 7.71(4 H, m), 7.26(1 H, dd,J = 11.00, 2.75 Hz), 7.11-7.19 (2 H, m), 7.05-7.11(1 H, m), 6.98(1 H, d,J = 4.95 Hz), 3.91(2 H, s), 1.38(6 H, s) 103

6 451 1H NMR (500 MHz, chloroform- d) δ ppm 7.67-7.75(4 H, m),7.18-7.25(2 H, m), 7.12(1 H, d, J = 4.40 Hz), 6.99(1 H, d, J= 4.40 Hz),6.91(1 H, d, J = 8.25 Hz), 3.85(2 H, s), 2.31(3 H, s), 1.39(6 H, s) 104

6 521 1H NMR (500 MHz, chloro- form-d) δ ppm 7.66-7.78(4 H, m),7.35-7.42(2 H, m), 7.08-7.17(2 H, m), 6.99(1 H, d, J = 4.40 Hz), 3.90(2H, s), 1.38(6 H, s). 105

6 462 1H NMR (500 MHz, chloroform- d) δ ppm 7.60-7.78(6 H, m),7.09-7.17(2 H, m), 6.95(1 H, d, J = 4.40 Hz), 3.97(2 H, s), 1.43(6 H. s)106

6 465 1H NMR (500 MHz, chloroform- d) δ ppm 7.71(4 H, d, J = 6.05 Hz),7.07-7.14(3 H, m), 6.98(1 H, d, J = 4.40 Hz), 3.64(2 H, s), 2.33(6 H,s), 1.40(6 H, s) 107

6 471 1H NMR (500 MHz, chloroform- d) δ ppm 7.67-7.74(4 H, m), 7.50 (1H, d, J = 2.47 Hz), 7.32(1 H, dd, J = 8.80, 2.47 Hz), 7.13(1 H, d, J =4.67 Hz), 7.03(1 H, d, J = 8.80 Hz), 6.97(1 H, d, J = 4.40 Hz), 3.91(2H, s), 1.40(6 H, s) 108

6 463 1H NMR (500 MHz, chloroform- d) δ ppm 7.64-7.77(4 H, m),7.19-7.24(2 H, m), 7.12(1 H, d, J = 4.40 Hz), 7.00(1 H, d, J = 4.40 Hz),6.94(1 H, d, J = 8.80 Hz), 4.16 (1 H, dd, J = 9.35, 3.30 Hz), 4.06 (1 H,dd, J = 9.35, 7.15 Hz), 3.31-3.42(1 H, m), 2.29(3 H, s), 0.99-1.11(1 H,m), 0.55-0.71 (2 H, m), 0.43-0.52(1 H, m), 0.29-0.41(1 H, m) 109

6 479 1H NMR (500 MHz, chloroform- d) δ ppm 7.61(2 H, d), 7.29(2 H, d, J= 7.97 Hz), 7.19-7.24(2 H, m), 7.11(1 H, d, J = 4.67 Hz), 6.98(1 H, d, J= 4.40 Hz), 6.94 (1 H, d, J = 8.52 Hz), 4.15(1 H, dd, J = 9.35, 3.30Hz), 4.05(1 H, dd, J = 9.35, 7.15 Hz), 3.30-3.42(1 H, m), 2.28(3 H, s),0.99-1.11(1 H, m), 0.55-0.70(2 H, m), 0.42-0.52(1 H, m), 0.30-0.39(1 H,m) 110

6 412 1H NMR (400 MHz, MeOD) δ ppm 8.67(1 H, d), 8.48(1 H, td, J = 7.91,1.51 Hz), 8.02(1 H, d, J = 8.28 Hz), 7.81-7.95(1 H, m), 7.07-7.29(4 H,m), 6.93(1 H, d, J = 8.78 Hz), 3.76(2 H, s), 3.35- 3.57(4 H, m), 2.22(3H, s), 1.27 (6 H, s) 111

6 397 1H NMR (500 MHz, methanol-d₃) δ ppm 7.32-7.40(3 H, m), 7.25-7.29(4 H, m), 7.16-7.23(2 H, m), 7.08(2 H, d, J = 8.80 Hz), 3.83 (2 H,s), 3.31(2 H, s), 2.89-3.03 (2 H, m), 1.32(6 H, s) 112

6 415 1H NMR (500 MHz, methanol-d₃) δ ppm 7.12-7.46(10 H, m), 3.90(1 H,s), 3.21-3.42(2 H, m), 2.90- 3.03(2 H, m), 1.33(6 H, s) 113

6 411 1H NMR (500 MHz, methanol-d₃) δ ppm 7.38(1 H, d, J = 4.40 Hz),7.;25-7.32(4 H, m), 7.16-7.24(4 H, m), 7.00(1 H, d, J = 8.25 Hz), 3.83(1H, s), 3.24-3.39(2 H, m), 2.90-3.05(2 H, m), 2.29(3 H, s), 1.35(6 H, s)114

6 431 1H NMR (500 MHz, methanol-d₃) δ ppm 7.56(1 H, d, J = 2.20 Hz),7.33-7.42(2 H, m), 7.17-7.31(7 H, m), 3.90(2 H, s), 3.23-3.42(2 H, m),2.89-3.08(2 H, m), 1.36 (6 H, s) 115

6 423 1H NMR (500 MHz, methanol-d₃) δ ppm 7.37(1 H, d, J = 4.40 Hz),7.25-7.32(4 H, m), 7.16-7.23(4 H, m), 7.03(1 H, d, J = 9.35 Hz),3.99-4.17(2 H, m), 3.25-3.39(3 H, m), 2.91-3.04(2 H, m), 2.28 (3 H, s),0.98-1.11(1 H, m), 0.51- 0.61(2H, m), 0.29-0.47(2 H, m) 116

6 445 1H NMR (500 MHz, methanol-d₃) δ ppm 7.30-7.39(2 H, m), 7.20-7.27(2 H, m), 7.01-7.13(4 H, m), 6.95(1 H, dd, J = 8.52, 2.47 Hz),3.86(2 H, s), 3.24-3.39(2 H, m), 2.97-3.11(2 H, m), 1.32 (6 H, s) 117

6 429 1H NMR (500 MHz, methanol-d₃) δ ppm 7.29-7.38(2 H, m), 7.17-7.26(4 H, m), 6.97-7.13(3 H, m), 3.83(2 H, s), 3.28-3.36(2 H, m), 3.04(2H, t, J = 7.42 Hz), 2.29(3 H, s), 1.35(6 H, s) 118

6 443 1H NMR (400 MHz, chloroform- d) δ ppm 7.16-7.35(5 H, m), 6.86-7.13(4 H, m), 3.84(2 H, s), 3.26- 3.41(2 H, m) ,3.07(2 H, t, J = 7.65Hz), 2.71(2 H, q, J = 7.53 Hz), 1.32-1.47(6 H, m), 1.23(3 H, t, J = 7.65Hz) 119

6 441 1H NMR (500 MHz, methanol-d₃) δ ppm 7.28-7.37(2 H, m), 7.16-7.26(4 H, m), 6.99-7.12(3 H, m), 3.95-4.38(2 H, m), 3.22- 3.42(3 H, m),3.04(2 H, t, J = 7.42 Hz), 2.27(3 H, s), 0.97-1.13(1 H, m), 0.46-0.63(2H, m), 0.29- 0.46(2 H, m) 120

6 457 1H NMR (500 MHz, methanol-d₃) δ ppm 7.20-7.30(2 H, m), 7.11-7.18(2 H, m), 6.92-7.04(4 H, m), 6.86(1 H, dd, J = 8.52, 2.47 Hz),3.85-4.12(2 H, m), 3.76(3 H, s), 3.16-3.31(3 H, m), 2.87- 3.03(2 H, m),0.82-1.00(1 H, m), 0.38-0.54(2 H, m), 0.18 0.37(2 H, m) 121

6 426 1H NMR (400 MHz, MeOD) δ ppm 8.29(1 H, d, J = 4.02 Hz), 7.60 (1 H,td, J = 7.65, 1.76 Hz), 7.16- 7.26(2 H, m), 6.98-7.14(4 H, m), 6.85(1 H,d, J = 9.03 Hz), 3.66 (2 H, s), 3.29(2 H, t, J = 7.28 Hz), 3.02(2 H, t,J = 7.40 Hz), 2.56(2 H, q, J = 7.53 Hz), 1.18(6 H, s), 1.05(3 H, t, J =7.53 Hz) 122

6 395 1H NMR (400 MHz, chloroform-d) δ ppm 7.62(2 H, d, J = 8.78 Hz),7.30(2 H, d, J = 8.03 Hz), 7.16(1 H, d, J = 4.52 Hz), 7.10(1 H, d, J =2.01 Hz), 6.91-7.05(2 H, m), 6.70(1 H, d, J = 8.53 Hz), 6.22(1 H, s),2.21(3 H, s) 123

6 449 1H NMR (500 MHz, chloroform- d) δ ppm 7.47(1 H, d, J = 2.47 Hz),7.21-7.32(4 H, m), 6.97-7.04 (3 H, m), 6.93(1 H, d, J = 4.67 Hz), 3.89(2H, s), 3.30(2 H, t, J = 7.70 Hz), 2.98(2 H, t, J = 7.84 Hz), 1.40(6 H,s) 124

6 429 1H NMR (400 MHz, chloroform- d) δ ppm 7.22-7.29(3 H, m), 7.16-7.22(2 H, m), 6.99(2 H, t, J = 8.66 Hz), 6.95(1 H, d, J = 4.40 Hz),6.88(1 H, d, J = 8.52 Hz), 3.84(2 H, s), 3.21-3.36(2 H, m), 2.90-3.08(2H, m), 2.29(3 H, s), 1.38(6 H, s) 125

6 443 1H NMR (500 MHz, chloroform-d) δ ppm 7.22-7.29(3 H, m), 7.17-7.22(2 H, m), 6.94-7.03(3 H, m), 6.90(1 H, d, J = 8.25 Hz), 3.84 (2 H, s),3.25-3.35(2 H, m), 2.92- 3.05(2 H, m), 2.71(2 H, q), 1.39 (6 H, s),1.23(3 H, t, J = 7.56 Hz) 126

6 457 1H NMR (500 MHz, chloroform- d) δ ppm 7.23-7.28(2 H, m),6.95-7.03(6 H, m), 6.90(1 H, dd, J = 8.52, 2.20 Hz), 4.20(1 H, dd, J =9.62, 2.75 Hz), 4.03(1 H, dd, J = 9.62, 8.25 Hz), 3.86(3 H, s),3.26-3.40(3 H, m), 2.93-3.06(2 H, m), 0.89-1.04(1 H, m), 0.52- 0.66(2 H,m), 0.41-0.49(1 H, m), 0.27-0.36(1 H, m) 127

6 441 1H NMR (500 MHz, chloroform-d) δ ppm 7.22-7.28(3 H, m), 7.16-7.22(2 H, m), 6.90-7.03(4 H, m), 4.14(1 H, dd, J = 9.35, 3.30 Hz),4.04(1 H, dd, J = 9.35, 7.15 Hz), 3.24-3.41(3 H, m), 2.93- 3.05(2 H, m),2.27(3 H, s), 0.99- 1.09(1 H, m), 0.55-0.70(2 H, m), 0.43-0.51(1 H, m),0.29- 0.39(1 H, m) 128

6 449 1H NMR (500 MHz, chloroform- d) δ ppm 7.47(1 H, d, J = 2.75Hz),7.21-7.34(3 H, m), 6.88-7.10 (5 H, m), 3.89(2 H, s), 3.27-3.37 (2 H,m), 2.97-3.06(2 H, m), 1.40(6 H, s) 129

6 429 1H NMR (500 MHz, chloroform- d) δ ppm 7.23-7.31(3 H, m),7.16-7.22(2 H, m), 6.88-7.09(4 H, m), 3.84(2 H, s), 3.27-3.35(2 H, m),2.96-3.05(2 H, m), 2.29(3 H, s), 1.38(6 H, s) 130

6 443 1H NMR (500 MHz, chloroform- d) δ ppm 7.24-7.30(2 H, m),7.17-7.22(2 H, m), 6.86-7.11(5 H, m), 3.84(2 H, s), 3.24-3.38(2 H, m),2.96-3.08(2 H, m), 2.71(2 H, q, J = 7.70 Hz), 1.38(6 H, s), 1.23(3 H, t,J = 7.56 Hz) 131

6 445 1H NMR (500 MHz, chloroform-d) δ ppm 7.20-7.38(2 H, m),6.83-7.14(7 H, m), 3.86(5 H, s), 3.23-3.40(2 H, m), 2.93-3.10 (2 H, m),1.36(6 H, s) 132

6 457 1H NMR (500 MHz, chloroform- d) δ ppm 7.24-7.31(2 H, m), 7.07 (1H, d, J = 7.42 Hz), 6.96-7.04(4 H, m), 6.87-6.96(2 H, m), 4.20 (1 H, dd,J = 9.62, 2.75 Hz, 4.03 (1 H, dd, J = 9.90, 8.25 Hz), 3.86(5 H, s),3.26-3.43(3 H, m), 2.96-3.06 (2 H, m), 0.91-1.03(1H, m), 0.52-0.68(2 H,m), 0.41-0.50(1 H, m), 0.26-0.35(1 H, m)

TABLE 2 3-Oxa substituted -1-arylpyrazin-2(1H)-ones

Aniline/Bromide Ex. No. Structure Component 133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

Alcohol Yield HNMR Data Ex. No. Component Method (%) HPLC LC-MS (CDCl₃)133

1 18 3.71 353 7.27(m, 5H), 6.93(m, 5H), 4.55(t, J = 7.5 Hz, 2H), 3.92(s,3H), 3.89(s, 3H), 3.17(t, J = 7.5 Hz, 2H). 134

1 26 3.96 387/389 7.25(m, 4H), 6.92(m, 5H), 4.52(t, J = 7.2 Hz, 2H),3.92(s, 3H), 3.89(s, 3H), 3.12(t, J = 7.2 Hz, 2H). 135

1 68 3.83 373/375 7.37(d, J = 8.4 Hz, 2H), 7.25(d, J = 8.4 Hz, 2H),6.60(m, 5H), 5.32(s, 2H), 3.84(s, 3H), 3.80(s, 3H) 136

7 445 1H NMR (500 MHz, chloroform-d) δ ppm 7.30(1 H, s), 7.22(3 H, d, J= 4.95 Hz), 6.94-7.00(2 H, m), 6.83- 6.91(3 H, m), 4.54(2 H, t, J = 7.42Hz), 3.85(5 H, s), 3.15(2 H, t, J = 7.42 Hz), 1.36(6 H, s) 137

4 3.59 403/405 7.42(d, J = 8.9 Hz, 2H), 7.18(d, J = 8.9 Hz, 2H), 7.02(m,2H), 6.80(d, J = 4.6 Hz, 1H), 6.93(dd, J = 2.2 and 8.4 Hz, 1H), 6.81(d,J = 4.6 Hz, 1H), 4.25 (m, 1H), 4.05(dd, J = 3.0 and 9.6 Hz, 1H), 3.88(s,3H), 3.86(dd, J = 1.0 and 9.6 Hz, 1H), 2.73(broad s, 1H), 1.27(d, J =4.3 Hz, 3H). 138

1 5 3.86 411 7.32(m, 5H), 7.23(m, 1H), 6.96(m, 2H), 6.87(m, 2H), 4.55(t,J = 2.0 Hz, 2H), 3.86(s, 5H), 3.18(t, J = 2.0 Hz, 2H), 1.35(s, 6H). 139

7 399 1H NMR (500 MHz, chloroform-d) δ ppm 7.23-7.38(4 H, m), 6.95-7.05(4 H, m), 6.84(2 H, s), 4.51(2 H, t, J = 7.29 Hz), 3.83(2 H, s), 3.14(2H, s), 1.36(6 H, s) 140

7 417 1H NMR (500 MHz, chloroform-d) δ ppm 7.25-7.30(2 H, m), 7.21(1 H,dd, J = 11.00, 2.47 Hz), 6.96-7.15(4 H, m), 6.75-6.90(2 H, m), 4.51(2 H,t, J = 7.29 Hz), 3.89(2 H, s), 3.13(2 H, t, J = 7.15 Hz), 1.38(6H, s)141

7 433 1H NMR (500 MHz, chloroform-d) δ ppm 7.45(1 H, d, J = 2.75 Hz),7.22- 7.35(3 H, m), 6.94-7.07(3 H, m), 6.75-6.88(2 H, m), 4.51(2 H, t, J= 7.15 Hz), 3.89(2 H, s), 3.13(2 H, t, J = 7.15 Hz), 1.40(6 H, s) 142

7 413 1H NMR (500 MHz, chloroform-d) δ ppm 7.24-7.31(2 H, m), 7.15-7.21(2 H, m), 6.99(2 H, t, J = 8.66 Hz), 6.89(1 H, d, J = 7.97 Hz), 6.83(2H, s), 4.50(2 H, t, J = 7.29 Hz), 3.84(2 H, s), 3.13(2H, t, J = 7.29Hz), 2.29(3 H, s), 1.38(6 H, s) 143

7 427 1H NMR (500 MHz, chloroform-d) δ ppm 7.24-7.31(2 H, m), 7.16-7.21(2 H, m), 6.99(2 H, t, J = 8.66 Hz), 6.90(1 H, d, J = 9.35 Hz),6.82-6.86 (2 H, m), 4.51(2 H, t, J = 7.29 Hz), 3.84(2 H, s), 3.14(2 H,t, J = 7.29 Hz), 2.71(2 H, q), 1.39(6 H, s), 1.24(3 H, t, J = 7.56 Hz)144

7 429 1H NMR (500 MHz, chloroform d) δ ppm 7.23-7.32(2 H, m), 6.94-7.03(4 H, m), 6.82-6.90(3 H, m), 4.51(2 H, t, J = 7.29 Hz), 5.85(5 H, s),3.14(2 H, t, J = 7.29 Hz), 1.36(6 H, s) 145

7 441 1H NMR (500 MHz, chloroform-d) δ ppm 7.24-7.32(2 H, m), 6.95-7.04(4 H, m), 6.83-6.91(3 H, m), 4.51(2 H, t, J = 7.29 Hz), 4.20(1 H, dd, J= 9.76, 2.89 Hz), 4.03(1 H, dd, J = 9.90, 8.25 Hz), 3.31-3.43(1 H, m),3.14(2 H, t, J = 7.29 Hz), 0.90- 1.05(1 H, m), 0.52-0.68(2 H, m),0.41-0.49(1 H, m), 0.26-0.35(1 H, m) 146

7 425 1H NMR (500 MHz, chloroform-d) δ ppm 7.25-7.31(2 H, m), 7.16-7.20(2 H, m), 6.95-7.02(2 H, m), 6.90- 6.94(1 H, m), 6.81-6.86(2 H, m),4.50(2 H, t, J = 7.29 Hz), 4.14(1 H, dd, J = 9.35, 3.30 Hz), 4.04(1 H,dd, J = 9.35, 7.15 Hz), 3.36(1 H, dt, J = 8.45, 3.61 Hz), 3.13(2 H, t, J= 7.15 Hz), 2.27(3 H, s), 0.99-1.09(1 H, m), 0.55-0.70(2 H, m),0.43-0.51 (1 H, m), 0.30-0.39(1 H, m) 147

7 415 1H NMR (500 MHz, chloroform-d) δ ppm 7.32(2 H, d), 7.23-7.29(4 H,m), 7.02(2 H, d), 6.84(2 H, s), 4.51 (2H, t, J = 7.29 Hz), 3.83(2 H, s),3.13 (2 H, t, J = 7.15 Hz), 1.36(6 H, s) 148

7 433 1H NMR (500 MHz, chloroform-d) δ ppm 7.18-7.31(5 H, m), 7.03-7.15(2 H, m), 6.75-6.89(2 H, m), 4.51(2 H, t, J = 7.15 Hz), 3.89(2 H, s),3.13(2 H, t, J = 7.15 Hz), 1.38(6 H, s) 149

7 449 1H NMR (500 MHz, chloroform-d) δ ppm 7.45(1 H, d, J = 2.75 Hz),7.22- 7.32(5 H, m), 7.00(1 H, d, J = 8.80 Hz), 6.77-6.90(2 H, m), 4.51(2H, t, J = 7.29 Hz), 3.89(2 H, s), 3.13(2 H, t, J = 7.15 Hz), 1.40(6 H,s) 150

7 429 1H NMR (500 MH, chloroform-d) δ ppm 7.23-7.30(4 H, m), 7.14-7.20(2 H, m), 6.88(1 H, d, J = 8.25 Hz), 6.83(2 H, s), 4.51(2 H, t, J = 7.15Hz), 3.84(2 H, s), 3.13(2 H, t, J = 7.15 Hz), 2.29(3 H, s), 1.38(6 H, s)151

7 443 1H NMR (500 MHz, chloroform-d) δ ppm 7.23-7.29(4 H, m), 7.16-7.21(2 H, m), 6.90(1 H, d, J = 9.35 Hz), 6.84(2 H, q, J = 4.49 Hz), 4.51(2H, t, J = 7.29 Hz), 3.84(2 H, s), 3.13(2 H, t, J = 7.29 Hz), 2.71(2 H,q, J = 7.51 Hz), 1.39(6 H, s), 1.23(3 H, t, J = 7.56 Hz) 152

7 445 1H NMR (500 MHz, chloroform-d) δ ppm 7.18-7.33(4 H, m), 6.93-7.04(2 H, m), 6.79-6.91(3 H, m), 4.51(2 H, t, J = 7.15 Hz), 3.85(5 H, s),3.14(2 H, t, J = 7.29 Hz), 1.36(6 H, s) 153

7 441 1H NMR (500 MHz, chloroform-d) δ ppm 7.23-7.29(4 H, m), 7.16-7.20(2 H, m), 6.92(1 H, d), 6.80-6.85(2 H, m), 4.51(2 H, t, J = 7.29 Hz),4.14 (1 H, dd, J = 9.35, 3.57 Hz), 4.04(1 H, dd, J = 9.35, 7.15 Hz),3.31-3.42(1 H, m), 3.13(2 H, t, J = 7.29 Hz), 2.27 (3 H, s), 0.97-1.11(1H, m), 0.55- 0.70(2 H, m), 0.42-0.51(1 H, m), 0.30-0.40(1 H, m) 154

7 457 1H NMR (500 MHz, chloroform d) δ ppm 7.23-7.29(4 H, m), 7.01(1 H,d, J = 8.30 Hz), 6.97(1 H, d, J = 2.47 Hz), 6.82-6.91(3 H, m), 4.51(2 H,t, J = 7.15 Hz), 4.20(1 H, dd, J = 9.76, 2.89 Hz), 4.03(1 H, dd, J =9.62, 8.25 Hz), 3.86(3 H, s), 3.30-3.41(1 H, m), 3.14(2 H, t, J = 7.15Hz), 0.89- 1.04(1 H, m), 0.52-0.68(2 H, m), 0.42-0.50(1 H, m),0.25-0.37(1 H, m) 155

7 429 1H NMR (500 MHz, chloroform-d) δ ppm 7.30(1 H, s), 7.16-7.25(5 H,m), 6.89(1 H, d, J = 8.52 Hz), 6.83(2 H, s), 4.53(2 H, t, J = 7.42 Hz),3.84(2 H, s), 3.14(2 H, t, J = 7.29 Hz), 2.29(3 H, s), 1.38(6 H, s) 156

7 443 1H NMR (500 MHz, chloroform-d) δ ppm 7.30(1 H, s), 7.16-7.25(5 H,m), 6.90(1 H, d, J = 9.35 Hz), 6.82- 6.87(2 H, m), 4.53(2 H, t, J = 7.42Hz), 3.84(2 H, s), 3.15(2 H, t, J = 7.29 Hz), 2.65-2.76(2 H, m),1.38(6H, s), 1.24(3 H, t, J = 7.56 Hz)

TABLE 3 3-Substituted-1-heteroarylpyrazin-2(1H)-ones

Aniline/Bromide Ex. No. Structure Component 157

158

159

160

161

162

163

164

165

166

167

168

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

Alcohol Yield HNMR Data Ex. No. Component Method (%) HPLC LC-MS (CDCl3)157

8 438 1H NMR (500 MHz, methanol-d₃) δ ppm 8.41(1 H, d, J = 2.47 Hz),8.09 (1 H, dd, J = 9.07, 2.75 Hz), 7.72- 7.79(4 H, m), 7.35(1 H, d, J =4.40 Hz), 7.24(1 H, d, J = 9.07 Hz), 7.19 (1 H, d, J = 4.67 Hz), 4.25(2H, s), 1.33(6 H, s). 158

8 454 1H NMR (500 MHz, methanol-d₃) δ ppm 8.25(1 H, d, J = 2.47 Hz),7.84 (1 H, dd, J = 8.80, 2.75 Hz), 7.63- 7.69(2 H, m), 7.37(2 H, d, J =7.97 Hz), 7.31(1 H, d, J = 4.40 Hz), 7.17 (1 H, d, J = 4.67 Hz),7.00(1H, d, J = 8.80 Hz), 4.19(2 H, s), 1.31(6 H, s) 159

8 398 1H NMR (400 MHz, methanol-d₃) δ ppm 8.23(1 H, d, J = 2.64 Hz),7.80 (1 H, dd, J = 8.90, 2.75 Hz), 7.39(1 H, d, J = 4.39 Hz) 7.15-7.33(6H, m), 6.98(1 H, d, J = 8.79 Hz), 4.18(2 H, s), 3.30-3.38(2 H, m), 2.91-3.08(2 H, m), 1.31(6 H, s) 160

8 416 1H NMR (400 MHz, methanol-d₃) δ ppm 8.22(1 H, d, J = 2.64 Hz),7.80 (1 H, dd, J = 8.90, 2.75 Hz), 7.37(1 H, d, J = 4.61 Hz),7.28-7.35(1 H, m), 7.17-7.28(2 H, m), 6.88-7.16 (3 H, m), 4.18(1 H, s),3.25-3.43(2 H, m), 3.04(2 H, t, J = 7.47 Hz), 1.30(6 H, s) 161

8 416 1H NMR (400 MHz, methanol-d₃) δ ppm 8.23(1 H, d, J = 2.64 Hz),7.80 (1 H, dd, J = 8.90, 2.75 Hz), 7.40(1 H, d, J = 4.61 Hz),7.23-7.34(2 H, m), 6.89-7.14(4 H, m), 4.18(1 H, s), 3.29-3.40(2 H, m),2.95-3.06 (2 H, m), 1.30(6 H, s) 162

8 416 1H NMR (400 MHz, methanol-d₃) δ ppm 8.15(1 H, d, J = 2.42 Hz),7.73 (1 H, dd, J = 8.90, 2.75 Hz), 7.31(1 H, d, J = 4.39 Hz),7.15-7.26(3 H, m), 6.85-7.00(3 H, m), 4.10(2 H, s), 3.22-3.29(2 H, m),2.89(2 H, t, J = 7.58 Hz), 1.23(6 H, s) 163

8 399 1H NMR (400 MHz, methanol-d₃) δ ppm 8.40-8.54(1 H, m), 8.22(1 H,d, J = 2.20 Hz), 7.72-7.86(2 H, m), 7.35-7.44(2 H, m), 7.23-7.32(2 H,m), 6.98(1 H, d, J = 9.01 Hz), 4.18(2 H, s), 3.47(2 H, t, J = 7.36 Hz),3.19(2 H, t, J = 7.36 Hz), 1.30(6 H, s) 164

8 472 1H NMR (500 MHz, chloroform-d) δ ppm 8.11(1 H, d, J = 2.47 Hz),7.89(1 H, d, J = 2.47 Hz), 7.71(4 H, s), 7.16(1 H, d, J = 4.40 Hz),6.95(1 H, d, J = 4.40 Hz), 4.30(2 H, s), 1.38(6 H, s) 165

8 488 1H NMR (500 MHz, chloroform-d) δ ppm 8.10(1 H, d, J = 2.47 Hz),7.88(1 H, d, J = 2.47 Hz), 7.61(2 H, d, J = 8.80 Hz), 7.30(2 H, d, J =7.97 Hz), 7.16(1 H, d, J = 4.67 Hz), 6.94(1 H, d, J = 4.40 Hz), 4.30(2H, s), 1.38(6 H, s) 166

8 432 1H NMR(400 MHz, chloroform-d) δ ppm 8.09(1 H, d, J = 2.42 Hz),7.86 (1 H, d, J = 2.64 Hz), 7.21-7.37(6 H, m), 6.91(1 H, d, J = 4.39Hz), 4.29(2 H, s), 3.28-3.43(2 H, m), 2.94- 3.09(2 H, m), 1.37(6 H, s)167

8 450 1H NMR(400 MHz, chloroform-d) δ ppm 8.08(1 H, d, J = 2.42 Hz),7.86 (1 H, d, J = 2.42 Hz), 7.16-7.33(3 H, m), 6.98-7.13(2 H, m), 6.90(1H, d, J = 4.61 Hz), 4.29(2 H, s), 3.29- 3.41(2 H, m), 3.07(2 H, t, J =7.69 Hz), 1.37(6 H, s) 168

8 450 1H NMR(500 MHz, chloroform-d) δ ppm 8.09(1 H, d, J = 2.20 Hz),7.86 (1 H, d, J = 2.47 Hz), 72.6-7.34(2 H, m), 7.06(1 H, d, J = 7.70Hz), 6.98- 7.03(1 H, m), 6.89-6.97(2 H, m), 4.29(2 H, s), 3.27-3.40(2 H,m), 2.94-3.10(2 H, m), 1.37(6 H, s) 168

8 450 1H NMR(500 MHz, chloroform-d) δ ppm 8.08(1 H, d, J = 2.47 Hz),7.86 (1 H, d, J = 2.47 Hz), 7.30(1 H, d, J = 4.40 Hz), 7.21-7.25(2 H,m), 7.00(2 H, t, J = 8.66 Hz), 6.91(1 H, d, J = 4.67 Hz), 4.29(2 H, s),3.23- 3.39(2 H, m), 2.91-3.05(2 H, m), 1.37(6 H, s) 169

8 433 1H NMR(500 MHz, chloroform-d) δ ppm 8.57(1 H, d, J = 3.85 Hz),8.08 (1 H, d, J = 2.47 Hz), 7.85(1 H, d, J = 2.47 Hz), 7.63(1 H, d, td,J = 7.63, 1.79 Hz), 7.31(1 H, d, J = 4.67 Hz), 7.24(1 H, d, J = 7.70Hz), 7.11-7.18(1 H, m), 6.90(1 H, d, J = 4.40 Hz), 4.29(2 H, s),3.45-3.59 (2 H, m), 3.22(2 H, t, J = 7.42 Hz), 1.37(6 H, s) 170

8 452 1H NMR(500 MHz, chloroform-d) δ ppm 8.00(1 H, d, J = 2.75 Hz),7.67- 7.76(4 H, m), 7.60(1 H, d, J = 1.92 Hz), 7.14(1 H, d, J = 4.40Hz), 6.96 (1 H, d, J = 4.40 Hz), 4.28(2 H, s), 2.30(3 H, s), 1.36(6 H,s) 171

8 468 1H NMR(500 MHz, chloroform-d) δ ppm 8.00(1 H, d, J = 2.75 Hz),7.57- 7.65(3 H, m), 7.29(2 H, d, J = 7.97 Hz), 7.14(1 H, d, J = 4.40Hz), 6.94 (1 H, d, J = 4.40 Hz), 4.28(2 H, s), 2.29(3 H, s), 1.35(6 H,s) 172

8 412 1H NMR(500 MHz, chloroform-d) δ ppm 7.98(1 H, d, J = 2.20 Hz),7.58 (1 H, d, J = 1.65 Hz), 7.27-7.36(5 H, m), 7.21-7.25(1 H, m), 6.91(1H, d, J = 4.40 Hz), 4.27(2 H, s), 3.27- 3.40(2 H, m), 2.95-3.11(2 H, m),2.28(3 H, s), 1.35(6 H, s) 173

8 430 1H NMR(500 MHz, chloroform-d) δ ppm 7.98(1 H, d, J = 2.75 Hz),7.58 (1 H, d, J = 1.92 Hz), 7.27-7.33(2 H, m), 7.18-7.24(1 H, m),7.00-7.12 (2 H, m), 6.91(1 H, d, J = 4.40 Hz), 4.27(2 H, s), 3.29-3.41(2H, m), 3.07(2 H, t, J = 7.70 Hz), 2.28(3 H, s), 1.35(6 H, s) 174

8 430 1H NMR(500 MHz, chloroform-d) δ ppm 7.98(1 H, d, J = 2.47 Hz),7.58 (1 H, d, J = 1.92 Hz), 7.27-7.32(1 H, m), 7.26(1 H, d, J = 7.70Hz), 7.06(1 H, d, J = 7.70 Hz), 6.98-7.04(1 H, m), 6.89-6.95(2 H, m),4.27(2 H, s), 3.25-3.38(2 H, m), 2.94-3.08 (2 H, m), 2.28(3 H, s),1.35(6 H, s) 175

8 430 1H NMR(500 MHz, chloroform-d) δ ppm 7.98(1 H, d, J = 2.75 Hz),7.58 (1 H, d, J = 1.92 Hz), 7.28(1 H, d, J = 4.67 Hz), 7.21-7.25(2 H,m), 7.00(2 H, t, J = 8.66 Hz), 6.91(1 H, d, J = 4.40 Hz0, 4.27(2 H, s),3.22- 3.38(2 H, m), 2.92-3.07(2 H, m), 2.28(3 H, s), 1.35(6 H, s) 176

8 413 1H NMR(500 MHz, chloroform-d) δ ppm 8.57(1 H, d, J = 3.85 Hz),7.97 (1 H, d, J = 2.20 Hz), 7.62(1 H, td, J = 7.63, 1.79 Hz), 7.57(1 H,d, J = 1.92 Hz), 7.29(1 H, d, J = 4.40 Hz), 7.24(1 H, d, J = 7.97 Hz),7.15 (1 H, dd, J = 6.60, 4.95 Hz), 6.90(1 H, d, J = 4.67 Hz), 4.27(2 H,s), 3.51 (2 H, t, J = 7.42 Hz), 3.22(2 H, t, J = 7.42 Hz), 2.27(3 H, s),1.35(6 H, s) 177

6 518 1H NMR(500 MHz, methanol-d₃) d ppm 8.08(1 H, d, J = 2.47 Hz), 7.93(1 H, d, J = 8.80 Hz), 7.65-7.74(3 H, m), 7.43(1 H, d, J = 4.67 Hz),7.38(2 H, d, J = 7.97 Hz), 7.22(1 H, d, J = 4.40 Hz), 6.98(1 H, d, J =1.10 Hz), 4.31(2 H, s), 2.66(3 H, d, J = 1.10 Hz), 1.34(6 H, s) 178

6 518 1H NMR(500 MHz, methanol-d₃) δ ppm 8.09(1 H, d, J = 9.35 Hz), 7.96(1 H, d, J = 2.47 Hz), 7.64-7.75(3 H, m), 7.29-7.49(3 H, m), 7.21(1 H,d, J = 4.40 Hz), 6.69(1 H, s), 4.38- 4.58(2 H, m), 2.54(3 H, s), 1.28(6H, s) 179

6 504 1H NMR(500 MHz, methanol-d₃) δ ppm 8.21(1 H, d, J = 8.80 Hz),7.90- 7.98(2 H, m), 7.73(1 H, dd, J = 8.80, 2.47 Hz), 7.67(2 H, d),7.35-7.42 (3 H, m), 7.21(1 H, d, J = 4.40 Hz), 7.11(1 H, d, J = 9.07Hz), 4.34(2 H, s), 1.35(6 H, s). 180

6 504 1H NMR(500 MHz, methanol-d₃) δ ppm 8.08(1 H, d, J = 9.35 Hz), 7.97(1 H, d, J = 9.35 Hz), 7.84(1 H, d, J = 2.47 Hz), 7.63-7.73(3 H, m),7.31-7.42(3 H, m), 7.20(1 H, d, J = 4.40 Hz), 6.78(1 H, d, J = 9.35 Hz),4.50(2 H, br s), 1.29(6 H, s) 181

6 502 1H NMR(400 MHz, chloroform-d) δ ppm 7.89-8.00(2 H, m), 7.68-7.79(4 H, m), 7.64(1 H, dd, J = 8.79, 2.42 Hz), 7.19(1 H, d, J = 4.39 Hz),7.11 (1 H, d, J = 4.39 Hz), 6.92(1 H, d, J = 0.88 Hz), 4.41(2 H, s),2.64(3 H, s), 1.36(6 H, s) 182

6 488 1H NMR(400 MHz, chloroform-d) δ ppm 8.06(1 H, d, J = 8.79 Hz),7.94 (1 H, d, J = 9.01 Hz), 7.85(1 H, d, J = 2.42 Hz), 7.64-7.78(5 H,m), 7.18(1 H, d, J = 4.61 Hz), 7.11(1 H, d, J = 4.39 Hz), 7.06(1 H, d, J= 9.01 Hz), 4.43(2 H, s), 1.38(6 H, s) 183

6 448 1H NMR(400 MHz, chloroform-d) δ ppm 8.04(1 H, d, J = 8.78 Hz),7.92 (1 H, d, J = 9.04 Hz), 7.83(1 H, d, J = 2.51 Hz), 7.65(1 H, dd, J =8.91, 2.38 Hz), 72.8-7.36(5 H, m), 7.20- 7.28(1 H, m), 7.02-7.09(2 H,m), 4.42(2 H, s), 3.28-3.44(2 H, m), 2.93-3.12(2 H, m), 1.37(6 H, s) 184

6 462 1H NMR(400 MHz, chloroform-d) δ ppm 7.88-7.98(2 H, m), 7.62(1 H,dd, J = 8.91, 2.38 Hz), 7.20-7.37(6 H, m), 7.07(1 H, d, J = 4.27 Hz),6.90 (1 H, s), 4.40(2 H, s), 3.30-3.39(2 H, m), 2.98-3.12(2 H, m),2.63(3 H, s), 1.35(6 H, s) 185

6 466 1H NMR(500 MHz, chloroform-d) δ ppm 8.04(1 H, d, J = 8.80 Hz),7.92 (1 H, d, J = 9.07 Hz), 7.83(1 H, d, J = 2.20 Hz), 7.65(1 H, dd, J =8.94, 2.34 Hz), 7.32(1 H, d, J = 4.40 Hz), 7.23-7.30(2 H, m),6.92-7.12(4 H, m), 4.42(2 H, s), 3.43-3.57(2 H, m), 3.25-3.33(2 H, m),2.91-3.08 (2 H, m), 1.37(6 H, s) 186

6 480 1H NMR(500 MHz, chloroform-d) δ ppm 7.88-7.97(2 H, m), 7.62(1 H,dd, J = 8.80, 2.47 Hz), 7.33(1 H, d, J = 4.40 Hz), 7.23-7.29(2 H, m),7.07(1 H, d, J = 4.40 Hz), 7.01(2 H, t, J = 8.66 Hz), 6.90(1 H, s),4.40(2 H, s), 3.27-3.38(2 H, m), 2.95- 3.08(2 H, m), 2.63(3 H, s),1.35(6 H, s) 187

6 466 1H NMR(500 MHz, chloroform-d) δ ppm 8.04(1 H, d, J = 8.80 Hz),7.92 (1 H, d, J = 9.07 Hz), 7.83(1 H, d, J = 2.47 Hz), 7.65(1 H, dd, J =8.80, 2.47 Hz), 7.34(1 H, d, J = 4.40 Hz), 7.27-7.31(1 H, m),6.99-7.10(4 H, m), 6.89-6.97(1 H, m), 4.42(2 H, s), 3.30-3.38(2 H, m),2.98- 3.08(2 H, m), 1.37(6 H, s) 188

6 480 1H NMR(500 MHz, chloroform-d) δ ppm 7.95(1 H, d, J = 2.20 Hz),7.91 (1 H, d, J = 8.80 Hz), 7.62(1 H, dd, J = 8.94, 2.34 Hz), 7.34(1 H,d, J = 4.67 Hz), 7.28(1 H, dd, J = 7.97, 1.92 Hz), 7.00-7.10(3 H, m),6.89- 6.97(2 H, m), 4.40(2 H, s), 3.28- 3.41(2 H, m), 2.97-3.10(2 H, m),2.63(3 H, s), 1.35(6 H, s) 189

6 477 1H NMR(500 MHz, methanol-d₃) δ ppm 8.28(1 H, s), 7.70-7.80(2 H,m), 7.55-7.61(2 H, m), 7.25-7.32 (4 H, m), 7.11(1 H, d, J = 4.40 Hz),4.19(2 H, s), 1.14(6 H, s) 190

6 477 1H NMR(500 MHz, methanol-d₃) δ ppm 8.30(1 H, s), 7.76-7.85(2 H,m), 7.65-7.71(2 H, m), 7.34-7.42 (3 H, m), 7.20(1 H, d, J = 4.40 Hz),4.29(2 H, s), 1.24(6 H, s) 191

7 466 1H NMR(500 MHz, chloroform-d₃) δ ppm 8.04(1 H, d, J = 8.80 Hz),7.92 (1 H,d , J = 8.80 Hz), 7.80(1 H, d, J = 2.47 Hz), 7.64(1 H, dd, J =8.94, 2.34 Hz), 7.23-7.30(4 H, m), 7.04 (1 H, d, J = 8.80 Hz), 6.95(1 H,d, J = 4.67 Hz), 6.90(1 H, d, J = 4.67 Hz), 4.54(2 H, t, J = 7.15 Hz),4.42(2 H, s), 3.15(2 H, t, J = 7.29 Hz), 1.37(6 H, s) 192

7 480 H NMR(500 MHz, chloroform-d) δ ppm 7.88-7.95(2 H, m), 7.61(1 H,dd, J = 8.80, 2.47 Hz), 7.27-7.30(4 H, m), 6.96(1 H, d, J = 4.67 Hz),6.90(2 H, d, J = 4.67 Hz), 4.54(2 H, t, J = 7.15 Hz), 4.40(2 H, s),3.15(2 H, t, J = 7.15 Hz), 2.62(3 H, s), 1.35(6 H, s)

Prodrugs were prepared of selected secondary and tertiary alcohols toimprove solubility and exposure. Standard conditions, employed togenerate amino acid esters of all but the glycine ester of the tertiaryalcohols, are exemplified in Example 193. Preparation of the glycineester of the tertiary alcohols is exemplified in Example 202.Preparation of a phosphate ester prodrug is exemplified by Example 204.

Example 1931-(2-Methoxy-4-(2-oxo-3-(4-(trifluoromethyl)phenylthio)pyrazin-1(2H)-yl)phenoxy)-2-methylpropan-2-yl2-aminoacetate

Part A.1-(2-Methoxy-4-(2-oxo-3-(4-(trifluoromethyl)phenylthio)pyrazin-1(2H)-yl)phenoxy)-2-methylpropan-2-yl2-(tert-butoxycarbonylamino)acetate

To a stirred suspension of the alcohol prepared in Example 36 (3.0 g,6.4 mmol), 4-pyrrolidinopyridine (0.95 g, 6.4 mmol) and BOC-glycine (3.4g, 19 mmol) in CH₂Cl₂ (60 mL) at 42° C. was addedN,N′-diisopropylcarbodiimide 3.0 mL, 19 mmol) over 3.5 h. After stirringat reflux for 2.5 h, HPLC analysis showed 25% alcohol still remained.More BOC-glycine (3.4 g, 19 mmol) was added followed by additionalN,N′-diisopropylcarbodiimide (3.0 mL, 19 mmol) which was slowly addedover 3.5 h; whereupon, HPLC analysis showed <5% alcohol remained. Thereaction was allowed to cool to RT prior to addition of hydrazinemonohydrate (18 mL, 370 mmol). After stirring for 5 minutes, thereaction mixture was cooled to 0° C. and filtered. The filtrates weresequentially washed with cold 1M HCl (3×20 mL) and cold 2% NaHCO₃ (3×20mL) prior to drying over MgSO₄ and concentrating under vacuum to afford5.6 g of crude product. Chromatography (silica gel 230-400 mesh,gradient elution: 0 to 60% EtOAc/hexane over 47 min) of the residueafforded the desired ester (3.9 g, 88% yield). HPLC 4.42 min. LC MS(M+1=624), H-NMR (CDCl₃) 7.72 (m, 4H), 7.12 (d, J=4.4 Hz, 1H), 7.02 (d,J=4.4 Hz, 1H), 7.00 (d, J=8.3 Hz, 1H), 6.99 (d, J=2.5 Hz, 1H), 6.90 (dd,J=2.5 and 8.3 Hz, 1H), 4.21 (s, 2H), 3.87 (s, 3H), 3.78 (m, 2H), 1.61(s, 6H), 1.45 (s, 9H).

Part B.1-(2-Methoxy-4-(2-oxo-3-(4-(trifluoromethyl)phenylthio)pyrazin-1(2H)-yl)phenoxy)-2-methylpropan-2-yl2-aminoacetate

The BOC'd glycinate ester described in Part A (3.9 g, 6.2 mmol) wastreated with 1:2 TFA/CH₂Cl₂ (145 mL) at RT for 25 min. After removal ofthe volatiles under vacuum, the residual TFA was removed byco-evaporation with CH₂Cl₂ (3×8 mL) and drying under vacuum for 20 min.Following dissolution in CH₂Cl₂ (70 mL), the solution was washed withcold 5% NaHCO₃ (3×30 mL) dried over MgSO₄ and concentrated to yield 3.3g of crude product. Purification by flash chromatography (120 g silicagel, 0 to 5% MeOH/CH₂Cl₂ over 24 min) afforded the desired free amine(2.5 g, 77% yield).). HPLC 3.72 min. LC MS 2.18 min (M+1=524), H-NMR(CDCl₃) 7.75 (d, J=8.7 Hz, 2H), 7.72 (d, J=8.7 Hz, 2H), 7.14 (d, J=4.4Hz, 1H), 7.02 (d, J=4.4 Hz, 1H), 7.00 (d, J=8.5 Hz, 1H), 6.99 (d, J=2.4Hz, 1H), 6.92 (dd, J=2.4 and 8.5 Hz, 1H), 4.24 (s, 2H), 3.89 (s, 3H),3.36 (m, 2H), 1.63 (s, 6H), 1.54 (broad s, 2H).

Examples 194 to 201

Examples 194 to 201 were prepared in a similar manner to Example 193using the appropriate alcohol and BOC glycine followed by TFA removal ofthe BOC group.

TABLE 4 Glycine Prodrug Esters Example Glycine ester HPLC ¹H-NMR No. ofExample No. (Met1) LC MS (CDCl₃) 194 38 3.86 540 7.55 (d, J = 9.3 Hz,2H), 7.27 (d, J = 9.3 Hz, 2H), 7.18 (d, J = 4.4 Hz, 1H), 7.06 (d, J =4.4 Hz, 1H), 7.01 (d, J = 2.2 Hz, 1H), 6.99 (d, J = 8.2 Hz, 1H), 6.86(dd, J = 2.2 and 8.2 Hz, 1H), 4.15 (s, 2H), 3.76 (s, 3H), 3.17 (s, 2H),1.50 (s, 6H). 195 32 3.59 470 7.47 (d, J = 8.7 Hz, 2H), 7.27 (d, J = 8.7Hz, 2H), 7.11 (d, J = 4.4 Hz, 1H), 6.98 (d, J = 2.3 Hz, 1H), 6.97 (d, J= 8.5 Hz, 1H), 6.95 (d, J = 4.4 Hz, 1H), 6.88 (dd, J = 2.3 and 8.5 Hz,1H), 4.20 (s, 2H), 3.86 (s, 3H), 3.33 (s, 2H), 2.40 (s, 3H), 1.50 (s,6H). 196 50 3.78 484 7.34 (d, J = 8.3 Hz, 2H), 7.22 (d, J = 8.3 Hz, 2H),7.05 (d, J = 4.4 Hz, 1H), 6.92 (d, J = 2.2 Hz, 1H), 6.90 (d, J = 8.2 Hz,1H), 6.87 (d, J = 4.4 Hz, 1H), 6.83 (dd, J = 2.2 and 8.2 Hz, 1H), 4.14(s, 2H), 3.79 (s, 3H), 3.27 (s, 2H), 2.63 (q, H = 7.7 Hz, 2H), 1.54 (s,6H), 1.19(t, J = 7.7 Hz, 3H). 197 65 482 7.25-7.09 (m, 8H), 6.87 (d, J =4.4 Hz, 1H), 6.80 (d, J = 9.4 Hz, 1H), 4.09 (s, 2H), 3.30 (2, 2H), 3.23(dd, J = 7.2, 9.8 Hz, 2H), 2.94 (dd, J = 7.2 and 8.2 Hz, 2H), 2.58 (q, J= 7.6 Hz, 2H), 1.55 (s, 6H), 1.13 (t, J = 7.6 Hz, 3H). 198 87 524 1H NMR(400 MHz, chloroform-d) δ ppm 8.40 (2H, br. s.), 7.59 (2H, d, J = 8.78Hz), 7.28 (2H, d, J = 8.03 Hz), 7.09-7.23 (3H, m), 6.97 (2H, d, J = 4.27Hz), 4.22 (2H, br. s.), 3.79 (2H, br. s.), 2.27 (3H, s), 1.62 (6H, s)199 88 544 1H NMR (500 MHz, methanol-d₃) δ ppm 7.65 (2H, d, J = 9.07Hz), 7.61 (1H, d, J = 2.47 Hz), 7.34-7.43 (3H, m), 7.23-7.29 (2H, m),7.16 (1H, d, J = 4.40 Hz), 4.38 (2H, s), 3.75 (2H, s), 1.68 (6H, s) 200123 486 1H NMR (500 MHz, methanol-d₃) δ ppm 7.38 (1H, d, J = 4.40 Hz),7.29 (2H, dd, J = 8.52, 5.50 Hz), 7.19-7.25 (3H, m), 6.98- 7.05 (3H, m),4.29 (2H, s), 3.74 (2H, s), 3.31-3.35 (2H, m), 2.98 (2H, t, J = 7.56Hz), 2.28 (3H, s), 1.67 (6H, s) 201 113 468 1H NMR (500 MHz,methanol-d₃) δ ppm 7.39 (1H, d, J = 4.40 Hz), 7.25-7.31 (4H, m),7.17-7.25 (4H, m), 7.03 (1H, d, J = 8.25 Hz), 4.28 (2H, s), 3.74 (2H,s), 3.24- 3.39 (2H, m), 2.91-3.04 (2H, m), 2.28 (3H, s), 1.67 (6H, s)

If desired the amino acid prodrug esters may be converted to thecorresponding HCl salt. For example, the HCl salt of Example 197 wasprepared by dissolving the compound (0.655 mg, 1.36 mmoles) in CH₂Cl₂(10 mL) and MeOH (1 mL) and cooling to −30° C. 1N HCl in ether (2.3 mL,1.7 eq) was added with stirring. Evaporation in vacuo afforded thedesired salt. (0.71 g). LC MS was identical to the free base. H-NMR(CD₃OD) 7.30 (d, J=4.4 Hz, 1H), 7.20 (m, 4H), 7.13 (m, 4H), 6.93 (d,J=8.5 Hz, 1H), 4.19 (s, 2H), 3.64 (s, 2H), 3.23 (dd, J=7.4, 15.4 Hz,2H), 2.90 (dd, J=8.0 and 15.4 Hz, 2H), 2.62 (q, J=7.5 Hz, 2H), 1.59 (s,6H), 1.14 (t, J=7.5 Hz, 3H).

Example 2021-(2-Methoxy-4-(2-oxo-3-(4-(trifluoromethyl)phenylthio)pyrazin-1(2H)-yl)phenoxy)propan-2-yl2-amino-3-methylbutanoate

To a stirred mixture of the alcohol described in Example 71 (0.882 g,1.949 mmol), 4-dimethylaminopyridine (0.714 g, 5.85 mmol) andN-(t-butoxycarbonyl)-L-valine (1.271 g, 5.85 mmol) in 18 mL of CH₂Cl₂ atrt was added WSC (1.121 g, 5.85 mmol). After stirring at ambienttemperature for 30 min, the reaction mixture was transferred to aseparatory funnel, washed with cold 5% H₂SO₄ (3×), 5% Na₂CO₃ (2×), andwater and dried over MgSO₄. Evaporation of the solvent afforded 1.03 gof crude product as the BOC amine. The crude product was dissolved in a1:2 mixture of TFA/CH₂Cl₂ (18 mL). After stirring for 15 min the solventwas evaporated in vacuo. The residue was transferred to a separatoryfunnel with CH₂Cl₂, washed with cold 5% Na₂CO₃ (2×), and dried overMgSO₄ to afford crude 790 mg of product after evaporation of thesolvent. The product was purified by flash chromatography (80 g silicagel, gradient elution: 1 to 8% MeOH/CH₂Cl₂ over 24 min) to afforded thedesired valine ester as a free base (0.69 g, 64% yield).

HPLC (Method 1) 3.84 min. LC MS 2.26 min (M+1=552), H-NMR (CDCl₃) 7.74(d, J=8.7 Hz, 2H), 7.72 (d, J=8.7 Hz, 2H), 7.13 (d, J=4.4 Hz, 1H), 7.02(d, J=4.4 Hz, 1H), 7.00 (d, J=8.5 Hz, 1H), 6.99 (d, J=2.4 Hz, 1H), 6.91(dd, J=2.4 and 8.5 Hz, 1H), 5.34 (m, 1H), 4.12 (m, 2H), 3.86 (d, 3H),3.30 (t, J=5.2 Hz, 1H), 2.05 (m, 1H), 1.40 (d, J=6.4 Hz), 0.98 (m, 3H),0.92 (m, 3H).

The HCl salt of Example 176 was prepared by dissolving the compound inCH₂Cl₂ (9 mL). After cooling the solution to −30° C., 1N HCl in ether(2.85 mL, 1.7 eq) was added with stirring. The yellow precipitate wascollected and dried to afford the HCl salt (0.74 g).

LC MS was identical to the free base. H-NMR (CDCl₃) 7.74 (d, J=8.7 Hz,2H), 7.79 (m, 4H), 7.33 (d, J=4.4 Hz, 1H), 7.18 (d, J=8.5 Hz, 1H), 7.15(d, J=2.4 Hz, 1H), 7.02 (dd, J=2.4 and 8.5 Hz, 1H), 5.51 (m, 1H), 4.24(m, 2H), 3.86 (d, 3H), 3.33 (s, 1H), 2.30 (m, 1H), 1.41 (d, J=6.4 Hz),1.12 (m, 6H).

Example 203(2S)-1,1,1-Trifluoro-3-(2-methoxy-4-(2-oxo-3-(4-(trifluoromethyl)phenylthio)pyrazin-1(2H)-yl)phenoxy)propan-2-yl2-amino-3-methylbutanoate

In an analogous fashion to that described in Example 202, the valineester of the alcohol described in Example 74 was prepared.

LC MS at t=2.35 min. (m+1=606) Phenomenex S5 C18 4.6×30 mmcolumn/water-MeOH-TFA 90:10:0.1 to 10:90:0.1 gradient over 2 min at 5mL/min with 1 min hold at the end of the gradient.

¹H NMR (500 MHz, CDCl₃) δ ppm 0.97 (dd, J=35.13, 6.92 Hz, 6H), 1.97-2.20(m, 1H), 3.42 (d, J=4.78 Hz, 1H), 3.86 (s, 4H), 4.26-4.36 (m, 1H), 4.44(dd, J=11.08, 3.53 Hz, 1H), 5.73-5.87 (m, 1H), 6.91 (dd, J=8.56, 2.27Hz, 1H), 6.97-7.06 (m, 2H), 7.13 (d, J=4.53 Hz, 1H), 7.58 (s, 1H),7.66-7.77 (m, 4H).

Example 204 Sodium3,3-difluoro-1-((2-methoxy-4-(2-oxo-3-(4-(trifluoromethoxy)-phenylthio)pyrazin-1(2H)-yl)phenoxy)methyl)cyclobutylphosphate

Part A. Dibenzyl3,3-difluoro-1-((2-methoxy-4-(2-oxo-3-(4-(trifluoromethoxy)phenylthio)pyrazin-1(2H)-yl)phenoxy)methyl)cyclobutylphosphate

To a mixture of dibenzyl diisopropylphosphoramidite (135 mg, 0.390mmol),1-(4-((3,3-difluoro-1-hydroxycyclobutyl)methoxy)-3-methoxyphenyl)-3-(4-(trifluoromethoxy)phenylthio)pyrazin-2(1H)-one(Example 75) (69 mg, 0.130 mmol) and 1H-1,2,4-triazole (27.0 mg, 0.390mmol) in DCE (20 mL) was stirred at reflux for 6 hours. The mixture wascooled to RT. 30% hydrogen peroxide in water (10 ml) was slowly addedand the mixture was stirred at RT for 30 min. The mixture was dilutedwith a solution of aqueous 10% sodium thiosulfate (40 ml) and wasextracted with DCM (50 ml). The DCM layer was dried over sodium sulfateand concentrated.

The crude product was purified by ISCO silica gel Column (40 g) and theproduct was eluted with hexane to 100% ethyl acetate in 10 min. Yielddibenzyl3,3-difluoro-1-((2-methoxy-4-(2-oxo-3-(4-(trifluoromethoxy)phenylthio)pyrazin-1(2H)-yl)phenoxy)methyl)cyclobutylphosphate (79 mg, 0.100 mmol, 77% yield) as off-white solid. 1H NMR (400MHz, chloroform-d) δ ppm 7.57-7.66 (2H, m), 7.27-7.39 (12 H, m), 7.13(1H, d, J=4.53 Hz), 6.81-7.00 (4H, m), 4.97-5.14 (4H, m), 4.29 (2H, s),3.75 (3H, s), 2.93-3.20 (4H, m).

Part B. Sodium3,3-difluoro-1-((2-methoxy-4-(2-oxo-3-(4-(trifluoromethoxy)phenylthio)pyrazin-1(2H)-yl)phenoxy)methyl)cyclobutylphosphate

To a solution of dibenzyl3,3-difluoro-1-((2-methoxy-4-(2-oxo-3-(4-(trifluoromethoxy)phenylthio)pyrazin-1(2H)-yl)phenoxy)methyl)cyclobutylphosphate (79 mg, 0.100 mmol) in TFA (2 mL) was stirred at RT for 3.5hours. The mixture was concentrated. The crude product was purified byprep-HPLC (Phenomenex, Luna 5 micron 25×250 mm, flow rate=30 ml/min.,gradient=20% A to 100% B in 10 min., A=90% H₂O/10% MeOH/0.1% TFA, B=10%H₂O/90% MeOH/0.1% TFA). Yield 46 mg, 0.075 mmol as yellow gum. Theyellow gum in ACN (2 ml) was added 0.5 N aqueous sodium bicarbonate (302μl, 0.151 mmol), the mixture was diluted with water (5 ml). The solutionwas then lyophilized. Yield sodium3,3-difluoro-1-((2-methoxy-4-(2-oxo-3-(4-(trifluoromethoxy)phenylthio)pyrazin-1(2H)-yl)phenoxy)methyl)cyclobutylphosphate (51.08 mg, 0.078 mmol, 78% yield) as off-white powder. MS(M+H=611). 1H NMR (400 MHz, MeOD) δ ppm 7.54-7.63 (2H, m), 7.19-7.33 (3H, m), 7.02-7.17 (3H, m), 6.91 (1H, dd, J=8.44, 2.39 Hz), 4.28 (2H, s),3.80 (3H, s), 3.13-3.32 (2H, m), 2.75-2.90 (2H, m).

Example 205 Sodium1-(2-methoxy-4-(2-oxo-3-(4-(trifluoromethoxy)phenylthio)pyrazin-1(2H)-yl)phenoxy)-2-methylpropan-2-ylphosphate

In an analogous fashion to that described in Example 204, the phosphateprodrug of the alcohol described in Example 38 was prepared. MS(M−H=561). 1H NMR (400 MHz, MeOD) δ ppm 7.57 (2H, d, J=8.56 Hz), 7.28(2H, d, J=8.31 Hz), 7.20 (1H, d, J=4.28 Hz), 6.97-7.12 (3H, m), 6.88(1H, dd, J=8.56, 2.27 Hz), 4.00 (2H, s), 3.78 (3H, s), 1.48 (6H, s).

The following experimental descriptions exemplify the preparation ofspecific compounds as set out in Examples 27, 95, 110, 113, and 124.

Example 27

1-(4-(2-Hydroxy-2-methylpropoxy)-3-methoxyphenyl)-3-(2-(pyridin-2-yl)-ethylthio)pyrazin-2(1H)-one

Following the procedures described in parts A-D of example 134,2-methoxy-4-nitrophenol was converted to1-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)pyrazine-2,3(1H,4H)-dione.A solution of1-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)pyrazine-2,3(1H,4H)-dioneprepared in Part ? (2.28 g, 7.44 mmol), EtN(iPr)₂ (3.9 mL, 22.3 mmol),PyBOP (6.78 g, 13.0 mmol) in DMF (35 mL) was stirred at ambienttemperature for 1.5 h. After addition of 2-pyridylethyl mercaptan (1.24g, 8.93 mmol), the reaction was stirred at ambient temperature. Afterstirring overnight the reaction mixture was partially concentrated underreduced pressure, quenching by addition of aq. NaHCO₃ and extracted withEtOAc. The EtOAc extracts were washed with brine, dried over MgSO₄ andconcentrated. Chromatography on silica employing a gradient elution with2.5-10% methanol/methylene chloride, followed by chromatography onsilica eluting with EtOAc, and trituration with EtOAc/Hexanes affordedthe desired product1-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)-3-(2-(pyridin-2-yl)ethylthio)pyrazin-2(1H)-one(2.15 g, 68% yield).

Example 95

1-(4-(2-Hydroxy-2-methylpropoxy)-3-methylphenyl)-3-(5-(trifluoromethyl)pyridin-2-ylthio)pyrazin-2(1H)-onePart A. 2-Methyl-1-(2-methyl-4-nitrophenoxy)propan-2-ol

A mixture of 2-methyl-4-nitrophenol (5.50 g, 35.9 mmol),2,2-dimethyloxirane (7.77 g, 108 mmol), K₂CO₃ (4.96 g, 35.9 mmol) andNaH₂PO₄ (4.31 g, 35.9 mmol) in MeCN (50 mL) and H₂O (8.82 mL) wasstirred at 140° C. in a steel bomb for 6 hours. After cooling to RT, thereaction was diluted with aq. saturated NaHCO₃ (80 ml) prior toextraction with EtOAc (100 ml). The EtOAc layer was dried over Na₂SO₄and concentrated. The crude product was purified by silica gelchromatography employing a solvent gradient (hexane to 60% ethylacetate) to elute 2-methyl-1-(2-methyl-4-nitrophenoxy)propan-2-ol (7.3g, 32.4 mmol, 90% yield) as yellow oil. MS (M+1=226). 1H NMR (500 MHz,chloroform-d) δ ppm 8.00-8.15 (2H, m), 6.86 (1H, d, J=8.80 Hz), 3.90(2H, s), 2.33 (3H, s), 1.40 (6H, s).

Part B. 1-(4-Amino-2-methylphenoxy)-2-methylpropan-2-ol

A mixture of 2-methyl-1-(2-methyl-4-nitrophenoxy)propan-2-ol (7.30 g,32.4 mmol) and 10% Pd/C (0.345 g, 3.24 mmol) in MeOH (150 mL) washydrogenated at 1 atm of H₂ for 18 hours. After removal of the Pd/C byfiltration, the solution was concentrated to yield1-(4-amino-2-methylphenoxy)-2-methylpropan-2-ol (6.10 g, 29.7 mmol, 92%yield) as clear gum which was carried forward without furtherpurification.

Part C.N1-(2,2-Dimethoxyethyl)-N2-(4-(2-hydroxy-2-methylpropoxy)-3-methylphenyl)oxalamide

Slow addition of a solution of ethyl 2-chloro-2-oxoacetate (4.69 g, 34.4mmol) in THF (30 ml) to a solution of1-(4-amino-2-methylphenoxy)-2-methylpropan-2-ol (6.10 g, 31.2 mmol) inTHF (100 mL) resulted in formation of a precipitate as the reactionstirred at RT for 30 min. At which time a solution of Et₃N (13.06 mL, 94mmol) and 2,2-dimethoxyethanamine (3.94 g, 37.5 mmol) in EtOAc (100 mL)was added prior to heating the mixture at reflux for 25 hours. Aftercooling and concentration under vacuum, the residue, following dilutionwith CH₂Cl₂, was extracted with aqueous 0.5 N HCl (2×150 ml). The CH₂Cl₂layer was dried over sodium sulfate and concentrated to yieldN1-(2,2-dimethoxyethyl)-N2-(4-(2-hydroxy-2-methylpropoxy)-3-methylphenyl)-oxalamide(11.40 g, 30.6 mmol, 98% yield) as white solid which was carried forwardwithout further purification.

Part D.3-Hydroxy-1-(4-(2-hydroxy-2-methylpropoxy)-3-methylphenyl)pyrazin-2(1H)-one

A solution ofN1-(2,2-dimethoxyethyl)-N2-(4-(2-hydroxy-2-methylpropoxy)-3-methylphenyl)oxalamide(11.4 g, 32.2 mmol) and TFA (2.97 mL, 38.6 mmol) in AcOH (120 mL) wasstirred at 135° C. in a seal tube for 60 min. After cooling andconcentration under vacuum, addition of CH₂Cl₂ (300 ml) produced aprecipitate which was collected by filtration and was washed with CH₂Cl₂(150 ml) to yield3-hydroxy-1-(4-(2-hydroxy-2-methylpropoxy)-3-methylphenyl)pyrazin-2(1H)-one(7.19 g, 23.53 mmol, 73.1% yield) as brown solid. MS (M+1=226). 1H NMR(500 MHz, methanol-d₃) δ ppm 7.13-7.26 (2H, m), 6.98 (1H, d, J=8.52 Hz),6.50 (1H, d, J=5.77 Hz), 6.41 (1H, d, J=6.05 Hz), 3.82 (2H, s), 2.29(3H, s), 1.35 (6H, s).

Part E.1-(4-(2-Hydroxy-2-methylpropoxy)-3-methylphenyl)-3-(5-(trifluoromethyl)-pyridin-2-ylthio)pyrazin-2(1H)-one

A mixture of3-hydroxy-1-(4-(2-hydroxy-2-methylpropoxy)-3-methylphenyl)pyrazin-2(1H)-one(100 mg, 0.344 mmol), PyBOP (314 mg, 0.603 mmol) and EtN(iPr)₂ (0.180mL, 1.033 mmol) in DMF (6 mL) was stirred at RT for 3 hours prior toaddition of 5-(trifluoromethyl)pyridine-2-thiol (74.1 mg, 0.413 mmol).After stirring for 3 days, The reaction was diluted with aq. saturatedNaHCO₃ (15 ml) prior to extraction with EtOAc (20 ml). The EtOAc layerwas dried over Na₂SO₄ and concentrated. The crude product was purifiedby prep-HPLC (Phenomenex, Luna 5 micron 30×250 mm, flow rate=30 ml/min.,gradient=20% A to 100% B in 30 min., A=90% H₂O/10% MeOH/0.1% TFA, B=10%H₂O/90% MeOH/0.1% TFA). After concentration, the residue in EtOAc (30ml) was converted to the free base by washing with aq. saturated NaHCO₃(30 ml). The EtOAc layer was dried over Na₂SO₄ and concentrated. Toyield1-(4-(2-hydroxy-2-methylpropoxy)-3-methylphenyl)-3-(5-(trifluoromethyl)pyridin-2-ylthio)pyrazin-2(1H)-one(22.76 mg, 14%) as off-white solid. MS (M+1=452). 1H NMR (500 MHz,chloroform-d) δ ppm 8.88 (1H, s), 7.89-7.99 (2H, m), 7.16-7.24 (3H, m),7.07 (1H, d, J=4.40 Hz), 6.90 (1H, d, J=8.52 Hz), 3.84 (2H, s), 2.30(3H, s), 1.39 (6H, s).

Example 110

1-(4-(2-Hydroxy-2-methylpropoxy)-3-methylphenyl)-3-(2-(pyridin-2-yl)ethylthio)pyrazin-2(1H)-one

A mixture of 3-(2-(pyridin-2-yl)ethylthio)pyrazin-2(1H)-one (100 mg,0.429 mmol), which was prepared by the procedure described in Method 7except for substitution of 2-(2-pyridylethylthiol) for2-(4-chlorophenethanol), 1-(4-bromo-2-methylphenoxy)-2-methylpropan-2-ol(133 mg, 0.514 mmol), N1,N2-dimethylethane-1,2-diamine (113 mg, 1.286mmol), K₃PO₄ (0.106 mL, 1.286 mmol) and copper(1) iodide (82 mg, 0.429mmol) in dioxane (1.0 mL) was stirred at 115° C. for 90 min. Thereaction mixture, after cooling to RT, was filtered and the filtrate wasconcentrated. The crude product was purified by silica gelchromatography employing a solvent gradient (hexane to 100% ethylacetate) to yield1-(4-(2-hydroxy-2-methylpropoxy)-3-methylphenyl)-3-(2-(pyridin-2-yl)ethylthio)pyrazin-2(1H)-one(140 mg, 0.340 mmol, 79% yield) as white solid. MS (M+H 412). 1H NMR(400 MHz, MeOD) δ ppm 8.67 (1H, d), 8.48 (1H, td, J=7.91, 1.51 Hz), 8.02(1H, d, J=8.28 Hz), 7.81-7.95 (1H, m), 7.07-7.29 (4H, m), 6.93 (1H, d,J=8.78 Hz), 3.76 (2H, s), 3.35-3.57 (4H, m), 2.22 (3H, s), 1.27 (6H, s).

Example 113

1-(4-(2-Hydroxy-2-methylpropoxy)-3-methylphenyl)-3-(phenethylthio)pyrazin-2(1H)-one

A mixture of 3-(phenethylthio)pyrazin-2(1H)-one (25 mg, 0.108 mmol),which was prepared by the procedure described in Method 7 except forsubstitution of 2-phenethylthiol for 2-(4-chlorophenethanol),1-(4-bromo-2-methylphenoxy)-2-methylpropan-2-ol (33.5 mg, 0.129 mmol),copper iodide (20.50 mg, 0.108 mmol), K₃PO₄ (70 mg, 0.323 mmol) andN,N′-dimethylethylenediamine (28.5 mg, 0.323 mmol) in dioxane (1.0 ml)was stirred at 115° C. for 2 hours. The reaction mixture, after coolingto RT, was filtered and the filtrate was concentrated. The crude productwas purified by silica gel chromatography employing a solvent gradient(hexane to 100% ethyl acetate) to elute to yield1-(4-(2-hydroxy-2-methylpropoxy)-3-methylphenyl)-3-(phenethylthio)-pyrazin-2(1H)-one(26.74 mg, 0.062 mmol, 57.5% yield) as off-white solid. MS (M+1=411). 1HNMR (500 MHz, methanol-d₃) δ ppm 7.38 (1H, d, J=4.40 Hz), 7.25-7.32 (4H,m), 7.16-7.24 (4H, m), 7.00 (1H, d, J=8.25 Hz), 3.83 (1H, s), 3.24-3.39(2H, m), 2.90-3.05 (2H, m), 2.29 (3H, s), 1.35 (6H, s).

Radioligand Binding Assay for Assessment of MCHR1 Activity Assay andBiological Evaluation

Compounds of Formula I were initially characterized in an in vitrobinding assay to determine their Ki or ability to antagonize binding ofa peptide agonist to the human melanin concentrating hormone receptor(MCHR1).

Radioligand Binding Assay for Assessment of MCHR1 Activity

Membranes from stably transfected HEK-293 cells expressing a mutated(E4Q, AST) hMCHR1 receptor were prepared by dounce homogenization anddifferential centrifugation. Binding experiments were carried out with0.5-1.0 ug of membrane protein incubated in a total of 0.2 ml in 25 mMHEPES (pH 7.4) with 10 mM MgCl₂, 2 mM EGTA, and 0.1% BSA (BindingBuffer) for 90 min. For competition binding assays, reactions werecarried out in the presence of with 0.06-0.1 nM [Phe^(n),[¹²⁵I]Tyr¹⁹]-MCH and increasing concentrations of unlabeled testmolecules. Reactions were terminated by rapid vacuum filtration over 96well-GFC Unifilter plates pre-coated with 0.075 ml binding buffercontaining 1% BSA, and washed 3 times with 0.4 ml of Phospho-bufferedSaline (pH 7.4) containing 0.01% TX-100. Filters were dried; 0.05 mlmicroscint 20 was added to each well and radioactivity was subsequentlyquantified by scintillation counting on a TopCount™ microplatescintillation counter (Packard). Inhibitory constants were determined bynonlinear least squares analysis using a four parameter logisticequation.

Biological Data

The following representative in vitro biological data was measured in abinding assay for the compounds from the Examples herein above:

Example Ki (nM) 113 8 124 9 65 10 110 17 125 17 131 18 38 20 181 21 6728 36 33 95 41 155 45 69 49 71 62 27 63 151 64 141 78 172 85 59 125 170132 10 141 46 232 178 290 3 576 169 1294 39 1580 157 1730 49 3043 193127 28 3153 40 3218 50 4664

Evaluation Of Prodrugs

The relative ability of the prodrug to enhance exposure(bioavailability) was assessed in an eight hour PK study usingcannulated Sprague Dawley (CD, Charles River Breeding Laboratory) rats.The compounds (parent and prodrug esters) were administered p.o. at 2.0ml/kg as a suspension in 0.5% methyl cellulose, 0.1% Tween 80 in waterat 10 mg/kg p.o. Blood samples were taken at 1, 2, 4 and 8 hr. Afterdetermination of parent concentration, an AUC was calculated for theeight hour study.

Assessment of In Vivo MCHR1 Activity

Male Sprague Dawley (CD, Charles River Breeding Laboratory) ratsweighing approximately 240 grams were placed in individual plastic cageswith AlphaDri bedding. The room was maintained at 72° F. and 50%humidity, and a 12/12 light dark cycle with lights out at 1600 hours.The rats were conditioned for 5 days prior to the start of the study tohaving a choice of foods. A normal chow (Harlan Teklad, 2018) thatcontains 18% protein, 5% fat and 73% carbohydrate and a high fat highsugar diet (Research Diets (D2327) that contains 20% protein, 40% fatand 40% carbohydrate where the carbohydrate is entirely sucrose and thefat is soybean and coconut oil. Studies have revealed that rats exhibita high preference for the high fat/high sucrose diet (80% preference).Body weight and consumption of both kinds of food as well as waterintake were measured daily. Water was available ad lib throughout thestudy. Food consumption is presented as daily caloric consumption whichis the sum of grams of chow multiplied by the Kcal per gram (3.5) plusgrams of high fat high sugar multiplied by Kcal per gram (4.59).

Baseline body weight was measured prior to drug treatment on day 0 ofthe study. Baseline food consumption was the average of the 3 days priorto the first drug treatment. Drug was administered daily p.o. at 2.0ml/kg at 1500 hours beginning on day 0 and continuing daily through day4 as a suspension in 0.5% methyl cellulose, 0.1% Tween 80 in water at3.0, 10 and 30 mg/kg p.o. All data were evaluated using ANOVA andFishers PLSD statistics.

Biological Data

Dose Weight Reduction Example (mg/kg) versus Vehicle 193 3 0.7% 10 2.1%30 3.4% 194 3 0.9% 10 2.7% 30 7.4% 202 30 2.2% 27 45 4.1% 113 45 4.2%

While the invention has been described according to several embodiments,various modifications thereto, in addition to those described herein,may become apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims.

1. A compound of Formula I or a pharmaceutically acceptable salt thereof

wherein

is a phenylene ring or a heteroaryl ring which contains one or twonitrogen atoms or one oxygen atom; R¹ is Z—Y—X—, wherein X is O, S,

Y is a bond, a 3- to 6-membered cycloalkyl, an alkyl chain; and Z isaryl or heteroaryl; R² is -E-G-(J)_(m) with m being an integer from 1 to3; E is O, S or a bond; G is lower alkyl, phenylalkyl, cycloalkyl,cycloalkylalkyl, alkylcycloalkyl, cycloalkoxy, alkylcycloalkoxy, orcycloalkoxyalkyl, and each J is independently hydrogen, hydroxyl, CN,—SO₂R⁷, —SR', —SOR⁷, lower alkyl, lower alkoxy, CF₃, CF₃O—, —COOR⁵, or—CO—NR^(5a)R⁶, wherein R^(5a) and R⁶ are each independently selectedfrom the group consisting of H, C₁₋₃ alkyl, and cycloalkyl, or R^(5a)and R⁶ taken together can be propanediyl, butanediyl or pentanediyl withthe N atom to which they are attached to form a 4-, 5- or 6-memberedcyclic amine which may be optionally substituted; R⁵ is H, C₁₋₆ alkyl,or cycloalkyl; R⁷ is lower alkyl; and R³ is C₁₋₆ alkyl, cycloalkyl, C₁₋₆alkoxy, halogen, hydrogen, —S—C₁₋₆ alkyl, CN, CF₃O, or CF₃; and whereinR² and R³ can be taken together to form a 5- to 7-membered ring which issaturated or partially unsaturated and may optionally include an Eheteroatom which is O or 0, 1 or 2 N atoms, which ring is substitutedwith one or two —O-G-(J)_(m) groups wherein at least one J is OH, andwhich may optionally be substituted with other substituents as set outfor “alkyl” or “heteroaryl”; with the proviso that where

is a phenylene group, E-G and R³ are not identical unsubstituted loweralkoxy groups, and when G is lower alkyl and J is H, R³ is not hydrogen;and R⁸ and R⁹ are each independently hydrogen, halogen, or lower alkyl;including esters thereof, prodrugs thereof, solvates thereof, and allstereoisomers thereof.
 2. The compound as defined in claim 1 wherein

is a phenylene or wherein

is a monocyclic or bicyclic heteroaryl ring.
 3. The compound as definedin claim 1 wherein

is


4. The compound as defined in claim 1 wherein

is


5. The compound as defined in claim 1 having the structure

or a pharmaceutically acceptable salt thereof or prodrug of any of theabove.
 6. The compound as defined in claim 4 wherein X is O or S; and/orR¹ is Z—Y—X, wherein Y is a bond or an alkylene chain of 1 to 3 atoms;and/or wherein Z is phenyl or aryl; wherein Z is heteroaryl; and/orwherein R² is -E-G-J; and/or wherein E is O or S; and/or wherein G is analkylene chain or alkylcycloalkyl; and/or wherein J is H, OH, SO₂R⁷,lower alkyl, lower alkoxy, or CF₃; and/or R³ is C₁₋₆ alkyl, C₁₋₆ alkoxy,H, or halo; and or R⁸ is H or alkyl; and/or R⁹ is H; and or R² and R³may optionally be taken together to form a 5- to 7-membered ring whichis saturated, unsaturated or partially unsaturated, and may include an Oatom or 1 or 2 N atoms, which ring is substituted with one or two—O-G-(J)_(m) groups wherein at least one J is OH, and which may beoptionally substituted with other substituents as set out for “alkyl” or“heteroaryl”.
 7. The compound as defined in claim 1 or apharmaceutically acceptable salt thereof


8. The compound as defined in claim 7 wherein R¹ is Z—Y—X; X is S;and/or Y is a bond or alkylene chain; and/or Z is phenyl or pyridyl;and/or E is O; and/or G is an alkylene chain or alkylcycloalkyl; and/orJ is H or OH; and/or R³ is H, alkoxy, alkyl, or halo; and/or R⁸ is H orCH₃; and/or R⁹ is H; wherein R² and R³ may be taken together to form a5- to 7-membered ring which is saturated, unsaturated or partiallyunsaturated, and may include an O atom or 1 or 2 N atoms, which ring issubstituted with 1 or 2-O-G-(J)_(m) groups wherein at least one J is OH,and which may be further optionally substituted with alkyl and/or OH. 9.The compound as defined in claim 1 wherein Z is aryl or heteroaryl, withany of the foregoing Z moieties either unsubstituted or substituted with1, 2 or 3 of amino, halo, C₁₋₆ alkyl, C₁₋₃ alkylamino, di-C₁₋₃alkylamino, C₁₋₃ alkoxy, C₁₋₃ thioalkyl, C₁₋₃ trifluoroalkoxy,trifluoromethyl, cycloalkyl, cycloalkoxy, or heteroaryl; and or J ishydrogen, hydroxyl, CN, —SO₂R⁷, —SR⁷, —SOR⁷, lower alkyl, lower alkoxy,CF₃, CF₃O—, —COOR⁵, or —CO—NR^(5a)R⁶, wherein R^(5a) and R⁶ are eachindependently selected from the group consisting of H, C₁₋₃ alkyl, andcycloalkyl, or R^(5a) and R⁶ taken together can be propanediyl,butanediyl or pentanediyl with the N atom to which they are attached toform a 4-, 5- or 6-membered cyclic amine optionally substituted withlower alkyl, lower alkoxy, hydroxyl, CF₃, or CF₃O.
 10. The compound ofclaim 1 wherein: Z is (1) aryl, which is optionally substituted with: a)halogen, b) alkyl, c) alkoxy, d) polyhaloalkyl, e) polyhaloalkoxy, f)amino, alkylamino or dialkylamino, g) alkylthio, h) OH, i) an ester, orj) aryl, (2) heteroaryl which is: a) pyridinyl, b) pyrazinyl, or c)pyrimidinyl, each of a), b) or c) being optionally substituted withalkyl, polyhaloalkyl, alkoxy, or halogen, (3) benzothiazole optionallysubstituted with halo or alkoxy, (4) benzoxazole optionally substitutedwith halo, (5) benzimidazole, (6) thiazole optionally substituted witharyl or alkyl, (7) indanyl, (8) quinolinyl optionally substituted withCF₃, or (9) imidazolidinyl; and/or Y is a bond or alkylene; and/or X isS, O, SO, or SO₂; and/or J is (1) H, (2) —CO—NR^(5a)R⁶ wherein R^(5a)and R⁶ together with the N to which they are attached form apyrrolidinyl ring, (3) OH, (4) COOH, (5) COOalkyl, (6) SO₂R⁷, or (7)prodrug esters which are selected from glycine

valine

and phosphate

and/or m is 1 or 2; and/or G is a bond or CH₂, (CH₂)₂, (CH₂)₃,

cycloalkoxy which is

or cycloalkoxy which is

E is O; and/or wherein R² and R³ can be optionally taken together toform a 5- or 6-membered unsaturated or aromatic ring containing one ortwo N atoms, which ring is optionally substituted with hydroxyalkylwhich is

and is

and wherein R² and R³ can optionally be taken together to form a6-membered saturated or partially unsaturated O-containing ring, whichring is optionally substituted with hydroxyalkyl, alkyl, and/or OH;and/or R³ is H, alkoxy, hydroxyalkyl, alkyl, halo, or hydroxyalkoxy;and/or R⁸ is H, halo or alkyl; and/or R⁹ is H.
 11. The compound of claim7, wherein Z is selected from the group consisting of phenyl, naphthyl,pyridinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, and benzoxazolyl. 12.The compound of claim 7, wherein R³ is C₁-C₆ alkoxy or C₁₋₆ alkyl. 13.The compound of claim 7, wherein R¹ is selected from the groupconsisting of:


14. The compound of claim 7 wherein

is a phenylene; and/or R² is

and/or R³ is methoxy or methyl; R¹ is selected from the group consistingof:


15. The compound as defined in claim 7 wherein X is S; Y is a bond or(CH₂)₂;

E-G-J is

R³ is CH₃O or CH₃; R⁸ is H; and R⁹ is H.
 16. The compound as defined inclaim 1 having the following formula:


17. The compound of claim 1 in a prodrug ester form, wherein R² is


18. A compound of Formula IB or a pharmaceutically acceptable saltthereof having the structure


19. The compound as defined in claim 18 wherein R¹ is Z—Y—X— wherein Xis S, Y is an alkyl chain of 1 to 3 carbons or a bond, Z is heteroarylor phenyl, each of which Z is optionally substituted with CF₃, CF₃O, orhalo; R² is -E-G-J wherein E is O, G is lower alkyl or alkylcycloalkyl,and J is OH; R³ is alkoxy, alkyl or halo; R⁸ is H or alkyl; and R⁹ is H.20. The compound as defined in claim 18 wherein X is S; Y is a bond or(CH₂)₂; Z is

R² is E-G-J which is

R³ is H, Cl, CH₃, or CH₃O; and R⁸ and R⁹ are each H.
 21. The compound ofclaim 1 wherein

is a heteroaryl ring; R² is

R³ is methoxy, Cl, H, or methyl; and R¹ is selected from the groupconsisting of:


22. A pharmaceutical composition comprising a therapeutically effectiveamount of a compound as defined in claim 1, alone or in combination withat least one additional therapeutic agent, in association with apharmaceutically acceptable carrier or diluent.
 23. A pharmaceuticalcombination comprising: at least one compound according to claim 1, andat least one additional therapeutic agent.
 24. The combination asdefined in claim 23 wherein the additional therapeutic agent is anacetyl-cholinesterase inhibitor, a muscarinic receptor-1 agonist, anicotinic agonist, a glutamic acid receptor (AMPA and NMDA) modulator, anootropic agent, an agent for Alzheimer's disease, an agent fortreatment of Parkinson's disease, anti-hyperlipidemia agent, ananti-obesity agent; anti-diabetic agent, appetite suppressant;cholesterol/lipid-lowering agent, HDL-raising agent, cognition enhancingagent, an agent used to treat neurodegeneration, an agent used to treatrespiratory conditions, an agent used to treat bowel disorders, ananti-inflammatory agent; anti-anxiety agent; an anti-depressant; ananti-hypertensive agent; an anti-sleep disorder agent; a cardiacglycoside; or an anti-tumor agent.
 25. The combination as defined inclaim 24 wherein the anti-obesity agent is a melanocortin receptor(MC4R) agonist, a cannabinoid receptor modulator, a growth hormonesecretagogue receptor (GHSR) antagonist, a galanin receptor modulator,an orexin antagonist, a CCK agonist, a GLP-1 agonist, aPre-proglucagon-derived peptides; an NPY1 or NPY5 antagonist, an NPY2 orNPY4 modulator, a corticotropin releasing factor agonist, a histaminereceptor-3 (H3) modulator, an aP2 inhibitor, a PPAR gamma modulator, aPPAR delta modulator, an acetyl-CoA carboxylase (ACC) inhibitor, an11-β-HSD-1 inhibitor, an adinopectin receptor modulator; a beta 3adrenergic agonist, a thyroid receptor beta modulator, a lipaseinhibitor, a serotonin receptor agonist, a monoamine reuptake inhibitoror releasing agent, an anorectic agent, a CNTF (ciliary neurotrophicfactor), a BDNF (brain-derived neurotrophic factor), a leptin and leptinreceptor modulator, or a cannabinoid-1 receptor antagonist, and theantidiabetic agent is an insulin secretagogue or insulin sensitizer,which is a biguanide, a sulfonyl urea, a glucosidase inhibitor, analdose reductase inhibitor, a PPAR γ agonist, a PPAR α agonist, a PPAR δantagonist or agonist, a PPAR α/γ dual agonist, an 11-β-HSD-1 inhibitor,a dipeptidyl peptidase IV (DP4) inhibitor, a SGLT2 inhibitor, a glycogenphosphorylase inhibitor, a meglitinide, a glucagon-like peptide-1(GLP-1), a GLP-1 agonist, and/or a PTP-1B inhibitor (protein tyrosinephosphatase-1B inhibitor), and wherein the additional therapeutic agentis an anti-hyperlipidemia agent, or agent used to treatarteriosclerosis, which is an HMG CoA reductase inhibitor, a squalenesynthetase inhibitor, a fabric acid derivative, aspirin, a bile acidsequestrant, an ACAT inhibitor, an upregulator of LDL receptor activity,a cholesterol absorption inhibitor, a cholesteryl transfer protein(CETP) inhibitor, an ileal Na+/bile acid cotransporter inhibitor, aphytoestrogen, a beta-lactam cholesterol absorption inhibitor, an HDLupregulator, a PPAR α-agonist and/or an FXR agonist; an LDL catabolismpromoter such, a sodium-proton exchange inhibitor, an LDL-receptorinducer or a steroidal glycoside, an anti-oxidant, or anantihomocysteine agent, isoniazid, an HMG-CoA synthase inhibitor, or alanosterol demethylase inhibitor, a PPAR δ agonist, or a sterolregulating element binding protein-I (SREBP-1), and theanti-hypertensive agent, which is a beta adrenergic blocker, a calciumchannel blocker (L-type and/or T-type), a diuretic, a renin inhibitor,an ACE inhibitor, an AT-1 receptor antagonist, an ET receptorantagonist, a Dual ET/AII antagonist, a neutral endopeptidase (NEP)inhibitor, a vasopeptidase inhibitor (dual NEP-ACE inhibitor) or anitrate; the sleep disorder agent is a melatonin analog, a melatoninreceptor antagonist, an ML 1 B agonist, a GABA receptor modulator, anNMDA receptor modulator, a histamine-3 (H3) receptor modulator, adopamine agonist or an orexin receptor modulator; an agent for treatingsubstance abuse or, addictive disorders which is a cannabinoid receptormodulator, a selective serotonin reuptake inhibitor (SSRI), methadone,buprenorphine, nicotine or bupropion; the anti-anxiety agents orantidepressants, which is a benzodiazepine, a 5HT1A receptor agonist, ora corticotropin releasing factor (CRF) antagonist; or a norepinephrinereuptake inhibitor (tertiary and secondary amine tricyclics), aselective serotonin reuptake inhibitor (SSRI), a monoamine oxidaseinhibitor (MAOI), a reversible inhibitor of monoamine oxidase (RIMA), aserotonin and norepinephrine reuptake inhibitor (SNRI), a corticotropinreleasing factor (CRF) receptor antagonist, an alpha-adrenoreceptorantagonist, or an atypical antidepressant.
 26. A method for treatingobesity, diabetes, arteriosclerosis, hypertension, polycystic ovarydisease, cardiovascular disease, osteoarthritis, dermatologicaldisorders, impaired glucose hemostasis, insulin resistance,hypercholesterolemia, hypertriglyceridemia, choletithiasis,dyslipidemia, bulimia nervosa and compulsive eating disorders; sleepdisorders; and psychiatric disorders, depression, anxiety,schizophrenia, substance abuse, cognition-enhancement or Parkinson'sdisease, which comprises administering to a patient in need oftreatment, a compound as defined in claim
 1. 27. The method as definedin claim 26 for treating obesity or Type II diabetes.
 28. A method oftreating Type II diabetes, which comprises administering to a patient inneed of treatment a compound as defined in claim
 1. 29. Use of acompound as defined in claim 1 in the manufacture of a medicament forthe treatment of diabetes.
 30. Use of a compound as defined in claim 1in the manufacture of a medicament for treatment of diabetes, in whichsuch treatment comprises a combination with another therapeutic agent,for concurrent or sequential use, in any order.
 31. Combination of acompound as defined in claim 1 and another therapeutic agent as amedicament for the treatment of diabetes.